Substituted monocyclic CGRP receptor antagonists

ABSTRACT

Compounds of formula I: 
                         
(wherein variables A 1 , A 2 , A 3 , A 4 , m, n, J, Q, R 4 , E a , E b , E c , R 6 , R 7 , R e , R f , R PG  and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. patent application Ser. No.11/800,626, filed May 7, 2007 now U.S. Pat. No. 7,629,338, which claimspriority under 35 U.S.C. 119(e) to U.S. Provisional Application No.60/799,071, filed May 9, 2006.

BACKGROUND OF THE INVENTION

CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-aminoacid peptide that is generated by tissue-specific alternate processingof calcitonin messenger RNA and is widely distributed in the central andperipheral nervous system. CGRP is localized predominantly in sensoryafferent and central neurons and mediates several biological actions,including vasodilation. CGRP is expressed in alpha- and beta-forms thatvary by one and three amino acids in the rat and human, respectively.CGRP-alpha and CGRP-beta display similar biological properties. Whenreleased from the cell, CGRP initiates its biological responses bybinding to specific cell surface receptors that are predominantlycoupled to the activation of adenylyl cyclase. CGRP receptors have beenidentified and pharmacologically evaluated in several tissues and cells,including those of brain, cardiovascular, endothelial, and smooth muscleorigin.

Based on pharmacological properties, these receptors are divided into atleast two subtypes, denoted CGRP₁ and CGRP₂. Human α-CGRP-(8-37), afragment of CGRP that lacks seven N-terminal amino acid residues, is aselective antagonist of CGRP₁, whereas the linear analogue of CGRP,diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selectiveagonist of CGRP₂. CGRP is a potent neuromodulator that has beenimplicated in the pathology of cerebrovascular disorders such asmigraine and cluster headache. In clinical studies, elevated levels ofCGRP in the jugular vein were found to occur during migraine attacks(Goadsby et al., Ann. Neurol., 1990, 28, 183-187), salivary levels ofCGRP are elevated in migraine subjects between attacks (Bellamy et al.,Headache, 2006, 46, 24-33), and CGRP itself has been shown to triggermigrainous headache (Lassen et al., Cephalalgia, 2002, 22, 54-61). Inclinical trials, the CGRP antagonist BIBN4096BS has been shown to beeffective in treating acute attacks of migraine (Olesen et al., NewEngl. J. Med., 2004, 350, 1104-1110) and was able to prevent headacheinduced by CGRP infusion in a control group (Petersen et al., Clin.Pharmacol. Ther., 2005, 77, 202-213).

CGRP-mediated activation of the trigeminovascular system may play a keyrole in migraine pathogenesis. Additionally, CGRP activates receptors onthe smooth muscle of intracranial vessels, leading to increasedvasodilation, which is thought to contribute to headache pain duringmigraine attacks (Lance, Headache Pathogenesis: Monoamines,Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers,1997, 3-9). The middle meningeal artery, the principle artery in thedura mater, is innervated by sensory fibers from the trigeminal ganglionwhich contain several neuropeptides, including CGRP. Trigeminal ganglionstimulation in the cat resulted in increased levels of CGRP, and inhumans, activation of the trigeminal system caused facial flushing andincreased levels of CGRP in the external jugular vein (Goadsby et al.,Ann. Neurol., 1988, 23, 193-196). Electrical stimulation of the duramater in rats increased the diameter of the middle meningeal artery, aneffect that was blocked by prior administration of CGRP(8-37), a peptideCGRP antagonist (Williamson et al., Cephalalgia, 1997, 17, 525-531).Trigeminal ganglion stimulation increased facial blood flow in the rat,which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669,93-99). Electrical stimulation of the trigeminal ganglion in marmosetproduced an increase in facial blood flow that could be blocked by thenon-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J. Pharmacol.,2000, 129, 420-423). Thus the vascular effects of CGRP may beattenuated, prevented or reversed by a CGRP antagonist.

CGRP-mediated vasodilation of rat middle meningeal artery was shown tosensitize neurons of the trigeminal nucleus caudalis (Williamson et al.,The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, andAdrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distentionof dural blood vessels during migraine headache may sensitize trigeminalneurons. Some of the associated symptoms of migraine, includingextra-cranial pain and facial allodynia, may be the result of sensitizedtrigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614-624). ACGRP antagonist may be beneficial in attenuating, preventing orreversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans. Suchdisorders include migraine and cluster headache (Doods, Curr Opin InvesDrugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14,320-327); chronic tension type headache (Ashina et al., Neurology, 2000,14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282);chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175); neurogenicinflammation and inflammatory pain (Holzer, Neurosci., 1988, 24,739-768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537-538;Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); eye pain (May etal. Cephalalgia, 2002, 22, 195-196), tooth pain (Awawdeh et al., Int.Endocrin. J., 2002, 35, 30-36), non-insulin dependent diabetes mellitus(Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders;inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, bronchialhyperreactivity, asthma, (Foster et al., Ann. NY Acad. Sci., 1992, 657,397-404; Schini et al., Am. J. Physiol., 1994, 267, H2483-H2490; Zhenget al., J. Virol., 1993, 67, 5786-5791); shock, sepsis (Beer et al.,Crit. Care Med., 2002, 30 (8), 1794-1798); opiate withdrawal syndrome(Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); morphinetolerance (Menard et al., J. Neurosci., 1996, 16 (7), 2342-2351); hotflashes in men and women (Chen et al., Lancet, 1993, 342, 49; Spetz etal., J. Urology, 2001, 166, 1720-1723); allergic dermatitis (Wallengren,Contact Dermatitis, 2000, 43 (3), 137-143); psoriasis; encephalitis,brain trauma, ischaemia, stroke, epilepsy, and neurodegenerativediseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15-34); skindiseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRCPress, Boca Raton, Fla.), neurogenic cutaneous redness, skinrosaceousness and erythema; tinnitus (Herzog et al., J. MembraneBiology, 2002, 189(3), 225); inflammatory bowel disease, irritable bowelsyndrome, (Hoffman et al. Scandinavian Journal of Gastroenterology,2002, 37(4) 414-422) and cystitis. Of particular importance is the acuteor prophylactic treatment of headache, including migraine and clusterheadache.

The present invention relates to compounds that are useful as ligandsfor CGRP receptors, in particular antagonists for CGRP receptors,processes for their preparation, their use in therapy, pharmaceuticalcompositions comprising them and methods of therapy using them.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of the formula I:

(wherein variables A¹, A², A³, A⁴, m, n, J, Q, R⁴, E^(a), E^(b), E^(c),R⁶, R⁷, R^(e), R^(f), R^(PG) and Y are as described herein) which areantagonists of CGRP receptors and which are useful in the treatment orprevention of diseases in which CGRP is involved, such as migraine. Theinvention is also directed to pharmaceutical compositions comprisingthese compounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which CGRP is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:A¹ is selected from:

-   -   (1) —O—,    -   (2) —S(O)_(v)—,    -   (3) —Si(OR^(a))—C₁₋₄alkyl-, where alkyl is unsubstituted or        substituted with 1-5 halo,    -   (4) —Si(C₁₋₄alkyl)₂, where each alkyl is independently        unsubstituted or substituted with 1-5 halo-,    -   (5) —CR⁶R⁷—,    -   (6) —N(R⁸)—,    -   (7) —(C═O)—,    -   (8) —C(R⁸)(R^(a))—,    -   (9) —C(N(R^(b))—SO₂R^(d))(R^(a))—,    -   (10) —C(N(R^(b))(C═O)R^(a))(R^(a))—,    -   (11) —C(N(R^(b))(C═O)OR^(a))(R^(a))—,    -   (12) —CR¹⁰R¹¹—, and    -   (13) —N(R¹¹)—;        A² is selected from:    -   (1) —CR⁶R⁷—,    -   (2) —CR¹⁰R¹¹—, and    -   (3) —(C═O)—;        A³ is selected from:    -   (1) —CR⁶R⁷—,    -   (2) —N(R⁸)—,    -   (3) —CR¹⁰R¹¹—, and    -   (4) —N(R¹¹)—;        A⁴ is selected from:    -   (1) —CR⁶R⁷—,    -   (2) —(C═O)—,    -   (3) —N(R⁸)—,    -   (4) —CR¹⁰R¹¹—,    -   (5) —N(R¹¹)—, and    -   (6) a bond between A² and A³;        E^(a) is selected from:    -   (1) —C(R^(5a))═,    -   (2) —N═, and    -   (3) —(N⁺—O⁻)═;        E^(b) is selected from:    -   (1) —C(R^(5b))═,    -   (2) —N═, and    -   (3) —(N⁺—O⁻)═;        E^(c) is selected from:    -   (1) —C(R^(5c))═,    -   (2) —N═, and    -   (3) —(N⁺—O⁻)═;        Q is selected from:    -   (1) —(C═O)—,    -   (2) —SO₂—,    -   (3) —SO—, and    -   (4) —C(R^(a))₂—;        R⁴ is selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —C₃₋₆cycloalkyl,        -   (c) —CF₃, and        -   (d) —O—R^(a),    -   (3) —C₃₋₆cycloalkyl,    -   (4) benzyl, and    -   (5) phenyl;        R^(5a), R^(5b) and R^(5c) are each independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        halo,    -   (3) halo,    -   (4) —OR^(a), and    -   (5) —CN;        R⁶ and R⁷ are each independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl or heterocycle, wherein said heterocycle is            selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, thienyl,            morpholinyl, thiazolyl, indolyl, indazolyl, benzimidazolyl,            and oxazolyl, which phenyl or heterocycle is unsubstituted            or substituted with 1-5 substituents each independently            selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (iii) —OR^(a),            -   (iv) —NR^(b)R^(c),            -   (v) —CN, and            -   (vi) oxo;        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(v)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —CF₃,        -   (m) —O—CO₂R^(d),        -   (n) —O—(C═O)—NR^(b)R^(c),        -   (o) —NR^(b)—(C═O)—NR^(b)R^(c), and        -   (p) —C(═O)R^(a),    -   (3) —C₃₋₈cycloalkyl, which is unsubstituted or substituted with        1-5 substituents each independently selected from:        -   (a) halo,        -   (b) —CN,        -   (c) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 halo, and        -   (d) —OR^(a),    -   (4) phenyl or heterocycle, wherein said heterocycle is selected        from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl,        piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and        oxazolyl, which phenyl or heterocycle is unsubstituted or        substituted with 1-5 substituents each independently selected        from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo, and            -   (iii) —OR^(a),        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(v)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —O—CO₂R^(d),        -   (m) —O—(C═O)—NR^(b)R^(c),        -   (n) —NR^(b)—(C═O)—NR^(b)R^(c),        -   (o) —C(═O)R^(a),        -   (p) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo, and        -   (q) oxo;    -   (5) halo,    -   (6) —OR^(a),    -   (7) —CN,    -   (8) —CO₂R^(a),    -   (9) —N(R^(b))C(═O)R^(a),    -   (10) —NR^(b)R^(c),    -   (11) —C(═O)NR^(b)R^(c), and    -   (12) —O(C═O)R^(a);    -   or R⁶ and R⁷ and the carbon atom or atoms to which they are        attached join to form a ring selected from cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,        cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,        cycloheptenyl, cyclooctenyl, dioxolanyl, dioxanyl, aziridinyl,        azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,        tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiapyranyl,        oxetanyl, thietanyl and tetrahydrothienyl, wherein the sulfur is        optionally oxidized to the sulfone or sulfoxide, which ring is        unsubstituted or substituted with 1-5 substituents each        independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-3 substituents each independently selected from:            -   (i) halo,            -   (ii) —OR^(a),            -   (iii) —C₃₋₆cycloalkyl,            -   (iv) —CO₂R^(a),            -   (v) —NR^(b)R^(c),            -   (vi) —S(O)_(v)R^(d),            -   (vii) —C(═O)NR^(b)R^(c), and            -   (viii) phenyl,        -   (b) —C₃₋₆cycloalkyl, wherein the C₃₋₆cycloalkyl group is            optionally fused to the ring, and which C₃₋₆cycloalkyl group            is unsubstituted or substituted with 1-3 substituents each            independently selected from:            -   (i) halo,            -   (ii) —OR^(a),            -   (iii) —C₃₋₆cycloalkyl,            -   (iv) —CO₂R^(a),            -   (v) —NR^(b)R^(c),            -   (vi) —S(O)_(v)R^(d),            -   (vii) —C(═O)NR^(b)R^(c), and            -   (viii) phenyl,        -   (c) phenyl or heterocycle, wherein heterocycle is selected            from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, thienyl,            morpholinyl, imidazolyl, furanyl, tetrahydrofuranyl,            thiazolyl and oxazolyl, wherein the phenyl or heterocycle is            optionally fused to the ring, and which phenyl or            heterocycle is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (iii) —OR^(a),            -   (iv) —CO₂R^(a),            -   (v) —O(C═O)R^(a),            -   (vi) —CN,            -   (vii) —NR^(b)R^(c),            -   (viii) oxo,            -   (ix) —C(═O)NR^(b)R^(c),            -   (x) —N(R^(b))C(═O)R^(a),            -   (xi) —N(R^(b))CO₂R^(a),            -   (xii) —O(C═O)NR^(b)R^(c), and            -   (xiii) —S(O)_(v)R^(d),        -   (d) —OR^(a),        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(v)R^(d),        -   (h) —CN,        -   (i) halo,        -   (j) —NR^(b)R^(c),        -   (k) —N(R^(b))C(═O)R^(a),        -   (l) —N(R^(b))SO₂R^(d),        -   (m) —O—CO₂R^(d),        -   (n) —O—(C═O)—NR^(b)R^(c),        -   (o) —NR^(b)—(C═O)—NR^(b)R^(c),        -   (p) —C(═O)R^(a), and        -   (q) oxo;            R⁸ is independently selected from:    -   (1) hydrogen,    -   (2) —C(═O)R^(a),    -   (3) —CO₂R^(a),    -   (4) —S(═O)R^(d),    -   (5) —SO₂R^(d),    -   (6) —C(═O)NR^(b)R^(c),    -   (7) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl or heterocycle, wherein said heterocycle is            selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, thienyl,            morpholinyl, thiazolyl and oxazolyl, which phenyl or            heterocycle is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo, and            -   (iii) —OR^(a),            -   (iv) —NR^(b)R^(c),            -   (v) —C(═O)R^(a),            -   (vi) —CO₂R^(a), and            -   (vii) oxo,        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(v)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —CF₃,        -   (m) —O—CO₂R^(d),        -   (n) —O—(C═O)—NR^(b)R^(c),        -   (o) —NR^(b)—(C═O)—NR^(b)R^(c), and        -   (p) —C(═O)R^(a),    -   (8) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 substituents each independently selected from:        -   (a) halo,        -   (b) —CN,        -   (c) —OR^(a), and        -   (d) C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo;    -   or R⁷ and R⁸ and the atoms to which they are attached join to        form a 4-, 5-, 6- or 7-membered alkyl- or heteroalkyl-ring        optionally containing an additional heteroatom selected from N,        O, and S, wherein the sulfur is optionally oxidized to the        sulfone or sulfoxide, which ring is unsubstituted or substituted        with 1-4 substituents each independently selected from:        -   (a) halo,        -   (b) phenyl, which is unsubstituted or substituted with 1-3            substituents each independently selected from: halo, OR^(a),            CN, and —C(═O)OR^(a),        -   (c) —OR^(a), and        -   (d) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo;            R¹⁰ is independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —CN,        -   (d) phenyl, and        -   (e) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 halo,    -   (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 halo;        R¹¹ is independently selected from the group consisting of:    -   phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl,        phenanthryl, anthryl, azepinyl, azepanyl, azetidinyl,        benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl,        benzopyranyl, benzothiopyranyl, benzofuryl, 1,3-benzodioxolyl,        benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl,        benzotriazolyl, chromanyl, cinnolinyl, dibenzofuranyl,        dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,        dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl,        imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl,        isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,        morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,        4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,        2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,        piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,        pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,        tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl,        tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,        thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl        sulfone, thiazolyl, thiazolinyl, thienofuryl, thienothienyl,        thienyl, triazolyl, isoxazolyl, tetrahydrothienyl,        tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, and        thietanyl, where R¹¹ is unsubstituted or substituted with 1-5        substituents each independently selected from R¹², R¹³, R¹⁴,        R^(15a) and R^(15b);        R¹², R¹³, R¹⁴, R^(15a) and R^(15b) are each independently        selected from:    -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl or heterocycle, wherein said heterocycle is            selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, thienyl,            morpholinyl, thiazolyl and oxazolyl, which phenyl or            heterocycle is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo, and            -   (iii) —OR^(a),        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(v)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —CF₃,        -   (m) —O—CO₂R^(d),        -   (n) —O—(C═O)—NR^(b)R^(c),        -   (o) —NR^(b)—(C═O)—NR^(b)R^(c), and        -   (p) —C(═O)R^(a),    -   (2) —C₁₋₆cycloalkyl, which is unsubstituted or substituted with        1-5 substituents each independently selected from:        -   (a) halo,        -   (b) —CN,        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (d) —OR^(a), and        -   (e) phenyl, which is unsubstituted or substituted with 1-5            substituents where the substituents are each independently            selected from:            -   (i) —OR^(a),            -   (ii) halo,            -   (iii) —CN, and            -   (iv) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,    -   (3) phenyl or heterocycle, wherein said heterocycle is selected        from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl,        piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and        oxazolyl, which phenyl or heterocycle is unsubstituted or        substituted with 1-5 substituents each independently selected        from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo, and            -   (iii) —OR^(a),        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(v)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —O—CO₂R^(d),        -   (m) —O—(C═O)—NR^(b)R^(c),        -   (n) —NR^(b)—(C═O)—NR^(b)R^(c),        -   (o) —C(═O)R^(a), and        -   (p) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,    -   (4) halo,    -   (5) oxo,    -   (6) —OR^(a),    -   (7) —CN,    -   (8) —CO₂R^(a),    -   (9) —C(═O)R^(a),    -   (10) —NR^(b)R^(c),    -   (11) —S(O)_(v)R^(d),    -   (12) —C(═O)NR^(b)R^(c),    -   (13) —O—CO₂R^(d),    -   (14) —N(R^(b))CO₂R^(d),    -   (15) —O—(C═O)—NR^(b)R^(c),    -   (16) —NR^(b)—(C═O)—NR^(b)R^(c),    -   (17) —SO₂NR^(b)R^(c),    -   (18) —N(R^(b))SO₂R^(d),    -   or R^(15a) and R^(15b) and the atom(s) to which they are        attached join to form a ring selected from cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridinyl,        azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,        thietanyl and tetrahydrothienyl, wherein the sulfur is        optionally oxidized to the sulfone or sulfoxide, which ring is        unsubstituted or substituted with 1-5 substituents each        independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-3 substituents each independently selected from:            -   (i) halo,            -   (ii) —OR^(a),            -   (iii) —C₃₋₆cycloalkyl,            -   (iv) —CO₂R^(a),            -   (v) —NR^(b)R^(c),            -   (vi) —S(O)_(v)R^(d),            -   (vii) —C(═O)NR^(b)R^(c), and            -   (viii) phenyl,        -   (b) phenyl or heterocycle, wherein said heterocycle is            selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, thienyl,            morpholinyl, thiazolyl and oxazolyl, which phenyl or            heterocycle is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo, and            -   (iii) —OR^(a),        -   (c) —OR^(a),        -   (d) halo,        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(v)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —O—CO₂R^(d),        -   (m) —O—(C═O)—NR^(b)R^(c),        -   (n) —NR^(b)—(C═O)—NR^(b)R^(c), and        -   (o) —C(═O)R^(a);            R^(PG) is independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl which is unsubstituted or substituted with 1-5        halo,    -   (3) —CH₂OR^(a),    -   (4) —CH₂—O—CH₂CH₂Si(CH₃)₃,    -   (5) —CH₂OP(═O)(OR^(c))₂,    -   (6) —(CH₂)_(k)-phenyl, which is unsubstituted or substituted        with 1-3 substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —CN, and        -   (d) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo;            J is independently selected from:    -   (1) ═C(R^(16a))—,    -   (2) —CR¹⁷R¹⁸—,    -   (3) —C(═O)—, and    -   (4) —N(R^(b))—;        Y is independently selected from:    -   (1) ═C(R^(16b))—,    -   (2) —CR¹⁷R¹⁸—,    -   (3) —C(═O)—,    -   (4) ═N—, and    -   (5) —N(R^(16b))—;        R¹⁷ and R¹⁸ are each independently selected from:    -   (1) hydrogen,    -   (2) halo,    -   (3) —OR^(a),    -   (4) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-4        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —CN,        -   (d) phenyl or heterocycle, wherein said heterocycle is            selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl,            piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl,            morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and            pyrazinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-5 substituents each independently            selected from:            -   (i) —OR^(a),            -   (ii) halo,            -   (iii) —CN,            -   (iv) —C₁₋₆alkyl which is unsubstituted or substituted                with 1-6 halo,    -   (5) phenyl or heterocycle wherein heterocycle is selected from        pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl,        azetidinyl, piperazinyl, pyrrolidinyl, morpholinyl,        tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl        or heterocycle is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —CN,        -   (c) —OR^(a),        -   (d) nitro,        -   (e) —C₁₋₆alkyl which is unsubstituted or substituted with            1-6 halo;    -   or R¹⁷ and R¹⁸ and the atom to which they are attached join to        form a 4-, 5-, or 6-membered ring optionally containing a        heteroatom selected from N, O, and S, wherein the sulfur is        optionally oxidized to the sulfone or sulfoxide, which ring is        unsubstituted or substituted with 1-4 substituents each        independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo, and        -   (d) phenyl;            R^(16a) and R^(16b) are each independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl or heterocycle, wherein said heterocycle is            selected from: imidazolyl, oxazolyl, pyridyl, pyrimidinyl,            pyrazinyl, pyridazinyl, piperidinyl, piperazinyl,            pyrrolidinyl, thiazolyl, thienyl, triazolyl, isoxazolyl and            morpholinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-3 substituents each independently            selected from:            -   (i) halo,            -   (ii) —OR^(a),            -   (iii) —CN, and            -   (iv) C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl,        pyridazinyl, tetrahydrofuryl, piperidinyl, piperazinyl,        pyrrolidinyl, azetidinyl, thiazolyl, thienyl, triazolyl,        isoxazolyl and morpholinyl, which phenyl or heterocycle is        unsubstituted or substituted with 1-3 substituents each        independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl,        -   (d) —C₁₋₄alkyl which is unsubstituted or substituted with            1-6 halo, and        -   (e) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo, and            -   (iii) —OR^(a),    -   (4) halo,    -   (5) —OR^(a),    -   (6) —CN,    -   (7) —CO₂R^(a),    -   (8) —NR^(b)R^(c), and    -   (9) —C(═O)NR^(b)R^(c);    -   or R^(16a) and R^(16b) and the atom(s) to which they are        attached join to form a ring selected from cyclopentenyl,        cyclohexenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl,        pyridazinyl, furanyl, dihydrofuranyl, dihydropyranyl, thiazolyl,        isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl,        thienyl, dihydrothienyl and dihydrothiopyranyl, which ring is        unsubstituted or substituted with 1-5 substituents each        independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-3 substituents each independently selected from:            -   (i) halo,            -   (ii) —OR^(a),            -   (iii) —C₃₋₆cycloalkyl,            -   (iv) phenyl or heterocycle, wherein heterocycle is                selected from pyridyl, pyrimidinyl, pyrazinyl,                pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl,                thienyl and morpholinyl, which phenyl or heterocycle is                unsubstituted or substituted with 1-5 substituents each                independently selected from:                -   (I) —OR^(a),                -   (II) halo,                -   (III) —CN, and                -   (IV) —C₁₋₆alkyl which is unsubstituted or                    substituted with 1-6 halo,            -   (v) —CO₂R^(a),            -   (vi) —NR^(b)R^(c),            -   (vii) —S(O)_(v)R^(d),            -   (viii) —C(═O)NR^(b)R^(c),            -   (ix) —N(R^(b))CO₂R^(a), and            -   (x) —N(R^(b))SO₂R^(d),        -   (b) phenyl or heterocycle, wherein said heterocycle is            selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, thienyl            and morpholinyl, which phenyl or heterocycle is            unsubstituted or substituted with 1-5 substituents each            independently selected from:            -   (i) halo,            -   (ii) —OR^(a),            -   (iii) —CN, and            -   (iv) —C₁₋₆alkyl which is unsubstituted or substituted                with 1-6 halo,        -   (c) halo,        -   (d) —S(O)_(v)R^(d),        -   (e) —OR^(a),        -   (f) —CN,        -   (g) —C(═O)R^(a),        -   (h) —NR^(b)R^(c),        -   (i) —C(═O)NR^(b)R^(c),        -   (j) —CO₂R^(a),        -   (k) —(NR^(b))CO₂R^(a),        -   (l) —O—(C═O)—NR^(b)R^(c),        -   (m) —(NR^(b))—(C═O)—NR^(b)R^(c),        -   (n) oxido,        -   (o) oxo, and        -   (p) —(NR^(b))SO₂R^(d);            R^(a) is independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl, which is unsubstituted or substituted with 1-7        substituents each independently selected from:        -   (a) halo,        -   (b) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,        -   (c) hydroxyl,        -   (d) —CN, and        -   (e) phenyl or heterocycle wherein said heterocycle is            selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl,            piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl,            morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and            pyrazinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-3 substituents each independently            selected from:            -   (i) halo,            -   (ii) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo,            -   (iii) —CN,            -   (iv) nitro,            -   (v) hydroxyl, and            -   (vi) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo,    -   (3) phenyl or heterocycle wherein said heterocycle is selected        from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl,        azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl,        tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl        or heterocycle is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (b) —CN,        -   (c) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,        -   (d) nitro,        -   (e) hydroxyl, and        -   (f) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo, and    -   (4) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 halo;        R^(b) and R^(c) are independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl, which is unsubstituted or substituted with 1-7        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —CN,        -   (d) —CO₂R^(a),        -   (e) phenyl or heterocycle, wherein said heterocycle is            selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl,            piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl,            morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and            pyrazinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-3 substituents each independently            selected from:            -   (i) halo,            -   (ii) —OR^(a),            -   (iii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo, and            -   (iv) nitro,    -   (3) phenyl or heterocycle, wherein said heterocycle is selected        from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl,        azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl,        tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl        or heterocycle is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,        -   (d) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 halo,        -   (e) —CN, and        -   (f) —CO₂R^(a),    -   (4) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 halo; or R^(b) and R^(c) and the nitrogen to which they are        attached join to form a 4-, 5-, or 6-membered ring optionally        containing an additional heteroatom selected from N, O, and S,        wherein the sulfur is optionally oxidized to the sulfone or        sulfoxide, which ring is unsubstituted or substituted with 1-4        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a), and        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo, and        -   (d) phenyl;            R^(d) is independently selected from:    -   (1) C₁₋₆alkyl, which is unsubstituted or substituted with 1-4        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —CO₂R^(a),        -   (d) —CN, and        -   (e) phenyl or heterocycle, wherein said heterocycle is            selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl,            piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl,            morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and            pyrazinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-3 substituents each independently            selected from:            -   (i) halo,            -   (ii) —OR^(a),            -   (iii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo, and            -   (iv) nitro,    -   (2) phenyl or heterocycle, wherein said heterocycle is selected        from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl,        azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl,        tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl        or heterocycle is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,        -   (d) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 halo        -   (e) —CN, and        -   (f) —CO₂R^(a), and    -   (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 halo;        R^(e) and R^(f) are independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-6        halo,    -   (3) phenyl, and    -   (4) benzyl;    -   or where R^(e) and R^(f) and the atom to which they are attached        join to form a 3-, 4-, 5-, or 6-membered ring optionally        containing a heteroatom selected from N, O, and S, wherein the        sulfur is optionally oxidized to the sulfone or sulfoxide, which        ring is unsubstituted or substituted with 1-4 substituents each        independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo, and        -   (d) phenyl;            m is 1, 2, or 3;            n is 1, 2, or 3;            v is 0, 1, or 2;            k is 0, 1, or 2;            and pharmaceutically acceptable salts thereof and individual            enantiomers and diastereomers thereof.

An embodiment of the invention includes compounds of formula Ia:

wherein A¹, A², A³, A⁴, m, n, J, Q, R⁴, E^(a), E^(b), E^(c), R⁶, R⁷,R^(PG) and Y are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the invention includes compounds of formula Ib:

wherein A¹, A², A³, J, Y, R⁴, E^(a), E^(b), E^(c), R⁶, R⁷, R^(PG), m andn are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the invention includes compounds of formula Ic:

wherein A¹, A², A³, J, Y, R⁴, E^(a), E^(b), E^(c), R⁶, R⁷, m and n aredefined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the invention includes compounds of formula Id:

wherein A¹, A², A³, J, Y, E^(a), E^(b), E^(c), R⁶, and R⁷ are definedherein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the invention includes compounds of formula Ie:

wherein A¹, A², A³, E^(a), E^(b), E^(c), R^(b), R⁶, and R⁷ are definedherein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the invention includes compounds of formula If:

wherein A¹, A², A³, E^(a), E^(b), E^(c), R⁶, R⁷, R¹⁷ and R¹⁸ are definedherein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the invention includes compounds of formula Ig:

wherein A¹, A², A³, E^(a), E^(b), E^(c), R⁶ and R⁷ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the invention includes compounds of formula Ih:

wherein A¹, E^(a), E^(b), E^(c), R⁶, R⁷, R¹⁰ and R¹¹ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

In an embodiment of the present invention A¹ is independently selectedfrom:

-   -   (1) —O—,    -   (2) —S(O)_(v)—,    -   (3) —Si(OR^(a))(—C₁₋₄alkyl, which is unsubstituted or        substituted with 1-5 halo)-,    -   (4) —Si(—C₁₋₄alkyl, which is unsubstituted or substituted with        1-5 halo)₂-,    -   (5) —CR⁶R⁷—,    -   (6) —N(R⁸)—,    -   (7) —(C═O)—,    -   (8) —C(R⁸)(R^(a))—,    -   (9) —C(N(R^(b))—SO₂R^(d))(R^(a))—,    -   (10) —C(N(R^(b))(C═O)R^(a))(R^(a))—,    -   (11) —C(N(R^(b))(C═O)R^(a))(R^(a))—,    -   (12) —CR¹⁰R¹¹—, and    -   (13) —N(R¹¹)—, wherein v, R⁶, R⁷, R⁸, R^(a), R^(b), R^(c),        R^(d), R¹⁰ and R¹¹ are defined herein.

In an embodiment of the present invention A¹ is independently selectedfrom:

-   -   (1) —O—,    -   (2) —S(O)_(v)—,    -   (3) —CR⁶R⁷—,    -   (4) —N(R⁸)—,    -   (5) —C(N(R^(b))(C═O)OR^(a))(R^(a))—,    -   (6) —(C═O)—, and    -   (7) —N(R¹¹)—, wherein v, R⁶, R⁷, R⁸, R^(a), R^(b), R^(c) and R¹¹        are defined herein.

In an embodiment of the present invention A¹ is —O—.

In an embodiment of the present invention A¹ is —S(O)_(v)—, wherein v isdefined herein.

In an embodiment of the present invention A¹ is —CR⁶R⁷—, wherein R⁶ andR⁷ are defined herein.

In an embodiment of the present invention A¹ is CH₂.

In an embodiment of the present invention A¹ is —N(R⁸)—, wherein R⁸ isdefined herein.

In an embodiment of the present invention A¹ is —NH—.

In an embodiment of the present invention A¹ is —C(OR^(a))H—, whereinR^(a) is defined herein.

In an embodiment of the present invention A¹ is —C(═O)—.

In an embodiment of the present invention A¹ is —C(NR^(b)R^(c))H—,wherein R^(b) and R^(c) are defined herein.

In an embodiment of the present invention A¹ is—C(N(R^(b))(C═O)OR^(a))H—, wherein R^(a) and R^(b) are defined herein.

In an embodiment of the present invention A² is independently selectedfrom:

-   -   (1) —CR⁶R⁷—,    -   (2) —CR¹⁰R¹¹—, and    -   (3) —(C═O)—, wherein R⁶, R⁷, R¹⁰ and R¹¹ are defined herein.

In an embodiment of the present invention A² is —CR⁶R⁷—, wherein R⁶ andR⁷ are defined herein.

In an embodiment of the present invention A² is —CH₂—.

In an embodiment of the present invention A² is —(C═O)—.

In an embodiment of the present invention A³ is independently selectedfrom:

-   -   (1) —CR⁶R⁷—,    -   (2) —CR¹⁰R¹¹—, and    -   (3) —N(R¹¹)—, wherein R⁶, R⁷, R¹⁰ and R¹¹ are defined herein.

In an embodiment of the present invention A³ is —CR⁶R⁷—, wherein R⁶ andR⁷ are defined herein.

In an embodiment of the present invention A³ is —CR¹⁰R¹¹—, wherein R¹⁰and R¹¹ are defined herein.

In an embodiment of the present invention A⁴ is independently selectedfrom:

-   -   (1) —CR⁶R⁷—,    -   (2) —CR¹⁰R¹¹,    -   (3) —N(R¹¹)—,    -   (4) —N(R⁸)—, and    -   (4) a bond between A² and A³, wherein R⁶, R⁷, R⁸, R¹⁰ and R¹¹        are defined herein.

In an embodiment of the present invention A⁴ is CH₂.

In an embodiment of the present invention A⁴ is a bond between A² andA³.

In an embodiment of the present invention E^(a) is independentlyselected from:

-   -   (1) —C(R^(5a))═,    -   (2) —N═, and    -   (3) —(N⁺—O⁻)═, wherein R^(5a) is defined herein.

In an embodiment of the present invention E^(a) is —C(R^(5a))═, whereinR^(5a) is defined herein.

In an embodiment of the present invention E^(a) is —C(H)═.

In an embodiment of the present invention E^(a) is —N═.

In an embodiment of the present invention E^(b) is independentlyselected from:

-   -   (1) —C(R^(5b))═,    -   (2) —N═, and    -   (3) —(N⁺—O⁻)═, wherein R^(5b) is defined herein.

In an embodiment of the present invention E^(b) is —C(R^(5b))═, whereinR^(5b) is defined herein.

In an embodiment of the present invention E^(b) is —C(H)═.

In an embodiment of the present invention E^(b) is —N═.

In an embodiment of the present invention E^(c) is independentlyselected from:

-   -   (1) —C(R^(5c))═,    -   (2) —N═, and    -   (3) —(N⁺—O⁻)═, wherein R^(5c) is defined herein.

In an embodiment of the present invention E^(c) is —C(R^(5c))═, whereinR^(5c) is defined herein.

In an embodiment of the present invention E^(c) is —C(H)═.

In an embodiment of the present invention E^(c) is —N═.

In an embodiment of the present invention Q is —(C═O)—.

In an embodiment of the present invention R⁴ is selected from: hydrogenand —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 fluoro.

In an embodiment of the present invention R⁴ is hydrogen.

In an embodiment of the present invention R^(5a), R^(5b) and R^(5c) areindependently selected from hydrogen, halo, and —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 fluoro.

In an embodiment of the present invention R^(5a), R^(5b) and R^(5c) areindependently selected from hydrogen and halo.

In an embodiment of the present invention R^(5a), R^(5b) and R^(5c) arehydrogen.

In an embodiment of the present invention R⁶ and R⁷ are independentlyselected from:

-   -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents where the substitutents are each independently        selected from: halo, phenyl, and —OR^(a),    -   (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-5 fluoro,    -   (4) phenyl or heterocycle, which is unsubstituted or substituted        with 1-5 halo, wherein heterocycle is defined herein,    -   (5) halo,    -   (6) —OR^(a),    -   (7) —NR^(b)R^(c), and    -   (8) —O(C═O)R^(a), wherein R^(a), R^(b) and R^(c) are defined        herein.

In an embodiment of the present invention R⁶ and R⁷ are independentlyselected from:

-   -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        fluoro,    -   (3) phenyl, which is unsubstituted or substituted with 1-5 halo,        and    -   (4) halo,    -   (5) —OR^(a), and    -   (6) —NR^(b)R^(c), wherein R^(a), R^(b) and R^(c) are defined        herein.

In an embodiment of the present invention R⁶ and R⁷ are independentlyselected from hydrogen, OH and —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-5 fluoro.

In an embodiment of the present invention R⁶ and R⁷ are independentlyselected from hydrogen, —NR^(b)R^(c) and —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 fluoro, wherein R^(b) and R^(c)are defined herein.

In an embodiment of the present invention R⁶ and R⁷ are independentlyselected from hydrogen, —NH₂ and —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-5 fluoro.

In an embodiment of the present invention R⁶ and R⁷ are independentlyselected from hydrogen and —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-5 fluoro.

In an embodiment of the present invention R⁶ and R⁷ are ethyl, which areunsubstituted or substituted with 1-5 fluoro.

In an embodiment of the present invention R⁶ and R⁷ are methyl, whichare unsubstituted or substituted with 1-3 fluoro.

In an embodiment of the present invention R⁶ and R⁷ and the carbon atomor atoms to which they are attached join to form a ring selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, dioxolanyl,dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, andpiperidinyl, which ring is unsubstituted or substituted with 1-6substituents each independently selected from:

-   -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        substituents where the substitutents are each independently        selected from: halo, —OR^(a), and phenyl,    -   (2) —C₃₋₆cycloalkyl, wherein the C₃₋₆cycloalkyl group is        optionally fused to the ring, and which C₃₋₆cycloalkyl group is        unsubstituted or substituted with 1-3 substituents each        independently selected from: halo, —OR^(a), and phenyl,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl,        piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and        oxazolyl, wherein the phenyl or heterocycle is optionally fused        to the ring, and which phenyl or heterocycle is unsubstituted or        substituted with 1-3 substituents each independently selected        from: halo, —OR^(a), and —C₁₋₄alkyl, which is unsubstituted or        substituted with 1-5 fluoro,    -   (4) halo,    -   (5) oxo,    -   (6) —CO₂R^(a), and    -   (7) —C(═O)R^(a),        wherein R^(a) is defined herein.

In an embodiment of the present invention R⁶ and R⁷ and the carbon atomor atoms to which they are attached join to form a ring selected fromcyclopropyl, cyclobutyl, cyclopentyl, dioxolanyl, cyclohexyl,cycloheptyl, cyclopentenyl, cyclohexenyl, tetrahydropyranyl,pyrrolidinyl, and piperidinyl, which ring is unsubstituted orsubstituted with 1-6 substituents each independently selected from:

-   -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        substituents where the substitutents are each independently        selected from: halo, and —OR^(a),    -   (2) phenyl or pyridyl, wherein the phenyl or pyridyl is        optionally fused to the ring, and which phenyl or pyridyl is        unsubstituted or substituted with 1-3 substituents each        independently selected from: halo, —OR^(a), and —C₁₋₄alkyl,        which is unsubstituted or substituted with 1-5 fluoro,    -   (3) halo, and    -   (4) —CO₂R^(a),        wherein R^(a) is defined herein.

In an embodiment of the present invention R⁶ and R⁷ and the carbon atomor atoms to which they are attached join to form a ring selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyranyl, pyrrolidinyl, and piperidinyl, which ring isunsubstituted or substituted with 1-6 substituents each independentlyselected from:

-   -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        halo,    -   (2) phenyl, wherein the phenyl is optionally fused to the ring,        and which phenyl is unsubstituted or substituted with 1-3        substituents each independently selected from: halo, —OR^(a),        and —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        fluoro, and    -   (3) halo,        wherein R^(a) is defined herein.

In an embodiment of the present invention R⁸ is selected from: hydrogen,—C(═O)R^(a), —CO₂R^(a), —SO₂R^(d), and —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 fluoro, wherein R^(a) and R^(d)are defined herein.

In an embodiment of the present invention R⁸ is selected from: hydrogen,and —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 fluoro.

In an embodiment of the present invention R⁸ is hydrogen.

In an embodiment of the present invention R⁸ is methyl

In an embodiment of the present invention R⁸ and R⁷ and the atoms towhich they are attached join to form a 4-, 5-, 6- or 7-membered alkyl-or heteroalkyl-ring optionally containing an additional heteroatomselected from N, O, and S, wherein the sulfur is optionally oxidized tothe sulfone or sulfoxide, which ring is unsubstituted or substitutedwith 1-4 substituents each independently selected from:

-   -   (1) halo,    -   (2) phenyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from: halo, OR^(a), CN,        and —C(═O)OR^(a),    -   (3) —OR^(a), and    -   (4) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        halo, wherein R^(a) is defined herein.

In an embodiment of the present invention R¹⁰ is selected from:hydrogen, and —C₁₋₆alkyl, which is unsubstituted or substituted withfluoro.

In an embodiment of the present invention R¹⁰ is hydrogen.

In an embodiment of the present invention R¹¹ is independently selectedfrom the group consisting of:

-   -   phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl,        phenanthryl, anthryl, azepinyl, azepanyl, azetidinyl,        benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl,        benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl,        benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl,        chromanyl, cinnolinyl, dibenzofuranyl, dihydrobenzofuryl,        dihydrobenzothienyl, dihydrobenzothiopyranyl,        dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl,        imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl,        isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,        morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,        4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,        2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,        piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,        pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,        tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl,        tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,        thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl        sulfone, thiazolyl, thiazolinyl, thienofuryl, thienothienyl,        thienyl, triazolyl, isoxazolyl, tetrahydrothienyl,        tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, and        thietanyl, where R¹¹ is unsubstituted or substituted with 1-5        substituents each independently selected from R¹², R¹³, R¹⁴,        R^(15a) and R^(15b), wherein R¹², R¹³, R¹⁴, R^(15a) and R^(15b)        are defined herein.

In an embodiment of the present invention R¹¹ is independently selectedfrom the group consisting of:

-   -   phenyl, furanyl, pyrazinyl, pyridinyl, pyridyl, pyrimidinyl,        pyrimidyl, tetrazolyl, thienyl, triazolyl, and isoxazolyl, where        R¹¹ is unsubstituted or substituted with 1-5 substituents each        independently selected from R¹², R¹³, R¹⁴, R^(15a) and R^(15b),        wherein R¹², R¹³, R¹⁴, R^(15a) and R^(15b) are defined herein.

In an embodiment of the present invention R¹¹ is independently selectedfrom the group consisting of:

-   -   phenyl, pyridyl, and thienyl, where R¹¹ is unsubstituted or        substituted with 1-5 substituents each independently selected        from R¹², R¹³, R¹⁴, R^(15a) and R^(15b), wherein R¹², R¹³, R¹⁴,        R^(15a) and R^(15b) are defined herein.

In an embodiment of the present invention R¹¹ is phenyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from R¹², R¹³, R¹⁴, R^(15a) and R^(15b), wherein R¹², R¹³, R¹⁴,R^(15a) and R^(15b) are defined herein.

In an embodiment of the present invention R^(PG) is selected from:

-   -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        halo,    -   (3) —CH₂OR^(a), and    -   (4) —CH₂—O—CH₂CH₂Si(CH₃)₃,    -   (5) —CH₂OP(═O)(OR^(c))₂,    -   wherein R^(a) and Ice are defined herein.

In an embodiment of the present invention R^(PG) is selected from:hydrogen and —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3halo.

In an embodiment of the present invention R^(PG) is methyl.

In an embodiment of the present invention R^(PG) is hydrogen.

In an embodiment of the present invention J is ═C(R^(16a))—, —CR¹⁷R¹⁸—or —N(R^(b))—, wherein R^(16a), R¹⁷, R¹⁸ and R^(b) are defined herein.

In an embodiment of the present invention J is ═C(R^(16a))—, whereinR^(16a) is defined herein.

In an embodiment of the present invention J is —CR¹⁷R¹⁸—, wherein R¹⁷and R¹⁸ are defined herein.

In an embodiment of the present invention J is —CH₂—.

In an embodiment of the present invention J is —N(R^(b))—, wherein R^(b)is defined herein.

In an embodiment of the present invention J is —N(CH₃)—.

In an embodiment of the present invention Y is ═C(R^(16b))—, —CR¹⁷R¹⁸—or —C(═O)—, wherein R^(16b), R¹⁷ and R¹⁸ are defined herein.

In an embodiment of the present invention Y is ═C(R^(16b))—, whereinR^(16b) is defined herein.

In an embodiment of the present invention Y is —C(═O)—.

In an embodiment of the present invention R^(16a) and R^(16b) areindependently selected from:

-   -   (1) hydrogen,    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from: halo, —OR^(a),        —C₃₋₆cycloalkyl, and phenyl,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, triazolyl,        isoxazolyl and morpholinyl, which phenyl or heterocycle is        unsubstituted or substituted with 1-3 substituents each        independently selected from: —C₁₋₄alkyl which is unsubstituted        or substituted with 1-3 halo, —OR^(a), and halo,    -   (4) halo,    -   (5) OR^(a), and    -   (6) —NR^(b)R^(c), wherein R^(a), R^(b) and R^(c) are defined        herein.

In an embodiment of the present invention R^(16a) and R^(16b) areindependently selected from:

-   -   (1) hydrogen,    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        fluoro, and    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, triazolyl,        isoxazolyl and morpholinyl.

In an embodiment of the present invention R^(16a) and R^(16b) and theatom(s) to which they are attached join to form a ring selected fromcyclohexenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,furanyl, oxazolyl, isoxazolyl, imidazolyl, and thienyl, which ring isunsubstituted or substituted with 1-3 substituents each independentlyselected from:

-   -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from: halo, OR^(a),        —CO₂R^(a), —NR^(b)R^(c), and CONR^(b)R^(c),    -   (2) phenyl or heterocycle, wherein heterocycle is selected from        pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl,        azetidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl,        which phenyl or heterocycle is unsubstituted or substituted with        1-3 substituents each independently selected from: halo, OR^(a)        and —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        fluoro,    -   (3) halo,    -   (4) OR^(a),    -   (5) —CN,    -   (6) —NR^(b)R^(c),    -   (7) CONR^(b)R^(c), and    -   (8) oxo, wherein R^(a), R^(b) and R^(c) are defined herein.

In an embodiment of the present invention R^(16a) and R^(16b) and theatom(s) to which they are attached join to form a ring selected fromphenyl, pyridyl, and pyrimidinyl, which ring is unsubstituted orsubstituted with 1-3 substituents each independently selected from:halo, OR^(a) and —C₁₋₄alkyl, which is unsubstituted or substituted with1-3 fluoro, wherein R^(a) is defined herein.

In an embodiment of the present invention R^(16a) and R^(16b) and theatom(s) to which they are attached join to form a ring selected frompyridyl, and pyrimidinyl.

In an embodiment of the present invention m is 1.

In an embodiment of the present invention n is 1.

In an embodiment of the present invention n is 2.

It is to be understood that where one or more of the above recitedstructures or substructures recite multiple substituents having the samedesignation each such variable may be the same or different from eachsimilarly designated variable. For example, if R⁸ is recited multipletimes in an embodiment of formula I, each instance of R⁸ in formula Imay independently be any of the substructures defined under R⁸. Theinvention is not limited to structures and substructures wherein each R⁸must be the same for a given structure. The same is true with respect toany variable appearing multiple times in a structure or substructure.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

The present invention includes compounds of formula I wherein one ormore hydrogen atoms are replaced by deuterium.

Tautomers of compounds defined in Formula I are also included within thescope of the present invention. For example, compounds includingcarbonyl —CH₂C(═O)— groups (keto forms) may undergo tautomerism to formhydroxyl —CH═C(OH)— groups (enol forms). Both keto and enol forms areincluded within the scope of the present invention.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As will be appreciated by those of skill in the art, not all of the R⁶and R⁷ substituents are capable of forming a ring structure. Moreover,even those substituents capable of ring formation may or may not form aring structure.

Also as appreciated by those of skill in the art, halo or halogen asused herein are intended to include chloro, fluoro, bromo and iodo.

As used herein, “alkyl” is intended to mean linear, branched and cyclicstructures having no carbon-to-carbon double or triple bonds. ThusC₁₋₆alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6carbons in a linear or branched arrangement, such that C₁₋₆alkylspecifically includes, but is not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl.“Cycloalkyl” is an alkyl, part or all of which forms a ring of three ormore atoms. C₀ or C₀alkyl is defined to identify the presence of adirect covalent bond.

The term “alkenyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon double bond, wherein hydrogen may be replaced by anadditional carbon-to-carbon double bond. C₂₋₆alkenyl, for example,includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.

The term “alkynyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon triple bond. Thus C₂₋₆alkynyl is defined to identifythe group as having 2, 3, 4, 5 or 6 carbons in a linear or branchedarrangement, such that C₂₋₆alkynyl specifically includes 2-hexynyl and2-pentynyl.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,napthyl, tetrahydronaphthyl, indanyl, or biphenyl.

The term “heterocycle” or “heterocyclic”, as used herein except wherenoted, represents a stable 4- to 8-membered monocyclic- or stable 8- to12-membered bicyclic heterocyclic ring system which is either saturatedor unsaturated, and which consists of carbon atoms and from one to sixheteroatoms selected from the group consisting of N, O, S, P and Si, andwherein the nitrogen, sulfur and phosphorus heteroatoms may optionallybe oxidized, and the nitrogen heteroatom may optionally be quaternized,and including any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring maybe attached at any heteroatom or carbon atom which results in thecreation of a stable structure. Examples of such heterocyclic groupsinclude, but are not limited to, azetidine, chroman, dihydrofuran,dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine,imidazolidinone, imidazoline, imidazolinone, indoline, isochroman,isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine,morpholine, morpholinone, oxazoline, oxazolidine, oxazolidinone,oxetane, 2-oxohexahydroazepin, 2-oxopiperazine, 2-oxopiperidine,2-oxopyrrolidine, piperazine, piperidine, pyran, pyrazolidine,pyrazoline, pyrrolidine, pyrroline, quinuclidine, tetrahydrofuran,tetrahydropyran, thiamorpholine, thiazoline, thiazolidine,thiomorpholine and N-oxides thereof.

The term “heteroaryl”, as used herein except where noted, represents astable 5- to 7-membered monocyclic- or stable 9- to 10-membered fusedbicyclic heterocyclic ring system which contains an aromatic ring, anyring of which may be saturated, such as piperidinyl, partiallysaturated, or unsaturated, such as pyridinyl, and which consists ofcarbon atoms and from one to six heteroatoms selected from the groupconsisting of N, O, S, P and Si, and wherein the nitrogen, sulfur andphosphorus heteroatoms may optionally be oxidized, and the nitrogenheteroatom may optionally be quaternized, and including any bicyclicgroup in which any of the above-defined heterocyclic rings is fused to abenzene ring. The heterocyclic ring may be attached at any heteroatom orcarbon atom which results in the creation of a stable structure.Examples of such heteroaryl groups include, but are not limited to,benzimidazole, benzisothiazole, benzisoxazole, benzofuran,benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline,cinnoline, furan, furazan, imidazole, indazole, indole, indolizine,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline,quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine,triazole, and N-oxides thereof.

The term “alkoxy,” as in C₁-C₆ alkoxy, is intended to refer to includealkoxy groups of from 1 to 6 carbon atoms of a straight, branched andcyclic configuration. Examples include methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativeswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. In one aspect of the invention the salts are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of Formula I are meant to also include thepharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which is selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual diastereomers thereof.

The subject compounds are useful in a method of antagonism of CGRPreceptors in a patient such as a mammal in need of such antagonismcomprising the administration of an effective amount of the compound.The present invention is directed to the use of the compounds disclosedherein as antagonists of CGRP receptors. In addition to primates,especially humans, a variety of other mammals can be treated accordingto the method of the present invention.

Another embodiment of the present invention is directed to a method forthe treatment, control, amelioration, or reduction of risk of a diseaseor disorder in which the CGRP receptor is involved in a patient thatcomprises administering to the patient a therapeutically effectiveamount of a compound that is an antagonist of CGRP receptors.

The present invention is further directed to a method for themanufacture of a medicament for antagonism of CGRP receptors activity inhumans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal, forexample a human being, male or female, in whom antagonism of CGRPreceptor activity is desired. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. As used herein, the term “treatment” refers both to thetreatment and to the prevention or prophylactic therapy of the mentionedconditions, particularly in a patient who is predisposed to such diseaseor disorder.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the terms “administrationof” or “administering a” compound shall encompass the treatment of thevarious conditions described with the compound specifically disclosed orwith a compound which may not be specifically disclosed, but whichconverts to the specified compound in vivo after administration to thepatient. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs,” ed. H. Bundgaard, Elsevier, 1985. Metabolites of thesecompounds include active species produced upon introduction of compoundsof this invention into the biological milieu.

The utility of the compounds in accordance with the present invention asantagonists of CGRP receptor activity may be demonstrated by methodologyknown in the art. Inhibition of the binding of ¹²⁵I-CGRP to receptorsand functional antagonism of CGRP receptors were determined as follows:

NATIVE RECEPTOR BINDING ASSAY: The binding of ¹²⁵I-CGRP to receptors inSK-N-MC cell membranes was carried out essentially as described(Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly,membranes (25 μg) were incubated in 1 mL of binding buffer [10 mM HEPES,pH 7.4, 5 mM MgCl₂ and 0.2% bovine serum albumin (BSA)] containing 10 pM¹²⁵I-CGRP and antagonist. After incubation at room temperature for 3 h,the assay was terminated by filtration through GFB glass fibre filterplates (PerkinElmer) that had been blocked with 0.5% polyethyleneiminefor 3 h. The filters were washed three times with ice-cold assay buffer(10 mM HEPES, pH 7.4 and 5 mM MgCl₂), then the plates were air dried.Scintillation fluid (50 μL) was added and the radioactivity was countedon a Topcount (Packard Instrument). Data analysis was carried out byusing Prism and the K_(i) was determined by using the Cheng-Prusoffequation (Cheng & Prusoff (1973) Biochem. Pharmacol. 22, 3099-3108).

RECOMBINANT RECEPTOR: Human CL receptor (Genbank accession numberL76380) was subcloned into the expression vector pIREShyg2 (BDBiosciences Clontech) as a 5′NheI and 3′ PmeI fragment. Human RAMP1(Genbank accession number AJ001014) was subcloned into the expressionvector pIRESpuro2 (BD Biosciences Clontech) as a 5′NheI and 3′NotIfragment. HEK 293 cells (human embryonic kidney cells; ATCC #CRL-1573)were cultured in DMEM with 4.5 g/L glucose, 1 mM sodium pyruvate and 2mM glutamine supplemented with 10% fetal bovine serum (FBS), 100units/mL penicillin and 100 μg/mL streptomycin, and maintained at 37° C.and 95% humidity. Cells were subcultured by treatment with 0.25% trypsinwith 0.1% EDTA in HBSS. Stable cell line generation was accomplished byco-transfecting 10 μg of DNA with 30 μg Lipofectamine 2000 (Invitrogen)in 75 cm² flasks. CL receptor and RAMP1 expression constructs wereco-transfected in equal amounts. Twenty-four hours after transfectionthe cells were diluted and selective medium (growth medium+300 μg/mLhygromycin and 1 μg/mL puromycin) was added the following day. A clonalcell line was generated by single cell deposition utilizing a FACSVantage SE (Becton Dickinson). Growth medium was adjusted to 150 μg/mLhygromycin and 0.5 μg/mL puromycin for cell propagation.

RECOMBINANT RECEPTOR BINDING ASSAY: Cells expressing recombinant humanCL receptor/RAMP1 were washed with PBS and harvested in harvest buffercontaining 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors(Roche). The cell suspension was disrupted with a laboratory homogenizerand centrifuged at 48,000 g to isolate membranes. The pellets wereresuspended in harvest buffer plus 250 mM sucrose and stored at −70° C.For binding assays, 20 μg of membranes were incubated in 1 ml bindingbuffer (10 mM HEPES, pH 7.4, 5 mM MgCl₂, and 0.2% BSA) for 3 hours atroom temperature containing 10 pM ¹²⁵I-hCGRP (GE Healthcare) andantagonist. The assay was terminated by filtration through 96-well GFBglass fiber filter plates (PerkinElmer) that had been blocked with 0.05%polyethyleneimine. The filters were washed 3 times with ice-cold assaybuffer (10 mM HEPES, pH 7.4 and 5 mM MgCl₂). Scintillation fluid wasadded and the plates were counted on a Topcount (Packard). Non-specificbinding was determined and the data analysis was carried out with theapparent dissociation constant (K_(i)) determined by using a non-linearleast squares fitting the bound CPM data to the equation below:

$Y_{obsd} = \frac{\begin{matrix}{{\left( {Y_{\max} - Y_{\min}} \right)\left( {{\%\mspace{14mu} I_{\max}} - {\%_{Imin}/100}} \right)} +} \\{Y_{\min} + {\left( {Y_{\max} - Y_{\min}} \right)\left( {100 - {\%\mspace{14mu}{I_{\max}/100}}} \right)}}\end{matrix}}{1 + \left( {\lbrack{Drug}\rbrack/{K_{i}\left( {1 + {\lbrack{Radiolabel}\rbrack/K_{d}}} \right)}^{nH}} \right.}$Where Y is observed CPM bound, Y_(max) is total bound counts, Y_(min) isnon specific bound counts, (Y_(max)−Y_(min)) is specific bound counts, %I_(max) is the maximum percent inhibition, % I min is the minimumpercent inhibition, radiolabel is the probe, and the K_(d) is theapparent dissociation constant for the radioligand for the receptor asdetermined by Hot saturation experiments.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in completegrowth medium at 85,000 cells/well in 96-well poly-D-lysine coatedplates (Corning) and cultured for ˜19 h before assay. Cells were washedwith PBS and then incubated with inhibitor for 30 min at 37° C. and 95%humidity in Cellgro Complete Serum-Free/Low-Protein medium (Mediatech,Inc.) with L-glutamine and 1 g/L BSA. Isobutyl-methylxanthine was addedto the cells at a concentration of 300 μM and incubated for 30 min at37° C. Human α-CGRP was added to the cells at a concentration of 0.3 nMand allowed to incubate at 37° C. for 5 min. After α-CGRP stimulationthe cells were washed with PBS and processed for cAMP determinationutilizing the two-stage assay procedure according to the manufacturer'srecommended protocol (cAMP SPA direct screening assay system; RPA 559;GE Healthcare). Dose response curves were plotted and IC₅₀ valuesdetermined from a 4-parameter logistic fit as defined by the equationy=((a−d)/(1+(x/c)^(b))+d, where y=response, x=dose, a=max response,d=min response, c=inflection point and b=slope.

In particular, the compounds of the following examples had activity asantagonists of the CGRP receptor in the aforementioned assays, generallywith a K_(i) or IC₅₀ value of less than about 50 μM. Such a result isindicative of the intrinsic activity of the compounds in use asantagonists of CGRP receptors.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of one ormore of the following conditions or diseases: headache; migraine;cluster headache; chronic tension type headache; pain; chronic pain;neurogenic inflammation and inflammatory pain; neuropathic pain; eyepain; tooth pain; diabetes; non-insulin dependent diabetes mellitus;vascular disorders; inflammation; arthritis; bronchial hyperreactivity,asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance;hot flashes in men and women; allergic dermatitis; psoriasis;encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skindiseases; neurogenic cutaneous redness, skin rosaceousness and erythema;inflammatory bowel disease, irritable bowel syndrome, cystitis; andother conditions that may be treated or prevented by antagonism of CGRPreceptors. Of particular importance is the acute or prophylactictreatment of headache, including migraine and cluster headache.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

For example, the present compounds may be used in conjunction with ananti-migraine agent, such as ergotamine and dihydroergotamine, or otherserotonin agonists, especially a 5-HT_(1B/1D) agonist, for examplesumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan,frovatriptan, donitriptan, and rizatriptan, a 5-HT_(1D) agonist such asPNU-142633 and a 5-HT_(1F) agonist such as LY334370; a cyclooxygenaseinhibitor, such as a selective cyclooxygenase-2 inhibitor, for examplerofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; anon-steroidal anti-inflammatory agent or a cytokine-suppressinganti-inflammatory agent, for example with a compound such as ibuprofen,ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam,piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac,oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept,tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate,olsalazine or sulfasalazine and the like; or glucocorticoids. Similarly,the instant compounds may be administered with an analgesic such asaspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone,acetyl methadol, buprenorphine or morphine.

Additionally, the present compounds may be used in conjunction with aninterleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2Bantagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptoragonist; a sodium channel blocker, for example lamotrigine; an opiateagonist such as levomethadyl acetate or methadyl acetate; a lipoxygenaseinhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptorantagonist, for example indoramin; an alpha receptor agonist; avanilloid receptor antagonist; a renin inhibitor; a granzyme Binhibitor; a substance P antagonist; an endothelin antagonist; anorepinephrin precursor; anti-anxiety agents such as diazepam,alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT₂ receptorantagonists; opiod agonists such as codeine, hydrocodone, tramadol,dextropropoxyphene and febtanyl; an mGluR5 agonist, antagonist orpotentiator; a GABA A receptor modulator, for example acamprosatecalcium; nicotinic antagonists or agonists including nicotine;muscarinic agonists or antagonists; a selective serotonin reuptakeinhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine,escitalopram, or citalopram; an antidepressant, for exampleamitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine,doxepin, protriptyline, desipramine, trimipramine, or imipramine; aleukotriene antagonist, for example montelukast or zafirlukast; aninhibitor of nitric oxide or an inhibitor of the synthesis of nitricoxide.

Also, the present compounds may be used in conjunction with gap junctioninhibitors; neuronal calcium channel blockers such as civamide; AMPA/KAantagonists such as LY293558; sigma receptor agonists; and vitamin B2.

Also, the present compounds may be used in conjunction with ergotalkaloids other than ergotamine and dihydroergotamine, for exampleergonovine, ergonovine, methylergonovine, metergoline, ergoloidmesylates, dihydroergocornine, dihydroergocristine, dihydroergocryptine,dihydro-α-ergocryptine, dihydro-β-ergocryptine, ergotoxine, ergocornine,ergocristine, ergocryptine, α-ergocryptine, β-ergocryptine, ergosine,ergostane, bromocriptine, or methysergide.

Additionally, the present compounds may be used in conjunction with abeta-adrenergic antagonist such as timolol, propanolol, atenolol,metoprolol or nadolol, and the like; a MAO inhibitor, for examplephenelzine; a calcium channel blocker, for example flunarizine,diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine,lomerizine, verapamil, nifedipine, or prochlorperazine; neurolepticssuch as olanzapine, droperidol, prochlorperazine, chlorpromazine andquetiapine; an anticonvulsant such as topiramate, zonisamide,tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine,gabapentin, pregabalin or divalproex sodium; an anti-hypertensive suchas an angiotensin II antagonist, for example losartan, irbesartin,valsartan, eprosartan, telmisartan, olmesartan, medoxomil, candesartanand candesartan cilexetil, an angiotensin I antagonist, an angiotensinconverting enzyme inhibitor such as lisinopril, enalapril, captopril,benazepril, quinapril, perindopril, ramipril and trandolapril; orbotulinum toxin type A or B.

The present compounds may be used in conjunction with a potentiator suchas caffeine, an H2-antagonist, simethicone, aluminum or magnesiumhydroxide; a decongestant such as oxymetazoline, epinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine;an antitussive such as caramiphen, carbetapentane, or dextromethorphan;a diuretic; a prokinetic agent such as metoclopramide or domperidone; asedating or non-sedating antihistamine such as acrivastine, azatadine,bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine,clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine,doxylamine, loratadine, phenindamine, pheniramine, phenyltoloxamine,promethazine, pyrilamine, terfenadine, triprolidine, phenylephrine,phenylpropanolamine, or pseudoephedrine. The present compounds also maybe used in conjunction with anti-emetics.

In a particularly preferred embodiment the present compounds are used inconjunction with an anti-migraine agent, such as: ergotamine ordihydroergotamine; a 5-HT₁ agonist, especially a 5-HT_(1B/1D) agonist,in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan,almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, andother serotonin agonists; and a cyclooxygenase inhibitor, such as aselective cyclooxygenase-2 inhibitor, in particular, rofecoxib,etoricoxib, celecoxib, valdecoxib or paracoxib.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of the presentinvention may be used in combination with other drugs that are used inthe prevention, treatment, control, amelioration, or reduction of riskof the diseases or conditions for which compounds of the presentinvention are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefore, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of the compound of the compound of the presentinvention to the other active ingredient(s) may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with another agent, the weightratio of the compound of the present invention to the other agent willgenerally range from about 1000:1 to about 1:1000, or from about 200:1to about 1:200. Combinations of a compound of the present invention andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s), and via thesame or different routes of administration.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, solutions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease. Oral tablets may also be formulated for immediate release, suchas fast melt tablets or wafers, rapid dissolve tablets or fast dissolvefilms.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensionsand the like, containing the compounds of the present invention areemployed. Similarly, transdermal patches may also be used for topicaladministration.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require antagonism of CGRP receptor activity anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. A suitable dosage level may be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to50 mg/kg per day. For oral administration, the compositions are may beprovided in the form of tablets containing 1.0 to 1000 milligrams of theactive ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0,75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0,800.0, 900.0, and 1000.0 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, ormay be administered once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing therisk of headache, migraine, cluster headache, or other diseases forwhich compounds of the present invention are indicated, generallysatisfactory results are obtained when the compounds of the presentinvention are administered at a daily dosage of from about 0.1 milligramto about 100 milligram per kilogram of animal body weight, given as asingle daily dose or in divided doses two to six times a day, or insustained release form. For most large mammals, the total daily dosageis from about 1.0 milligrams to about 1000 milligrams, or from about 1milligrams to about 50 milligrams. In the case of a 70 kg adult human,the total daily dose will generally be from about 7 milligrams to about350 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein.

The compounds of the present invention can be prepared readily accordingto the following Schemes and specific examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art but are not mentioned in greater detail. Thegeneral procedures for making the compounds claimed in this inventioncan be readily understood and appreciated by one skilled in the art fromviewing the following Schemes.

Lactam 1 can be deprotonated with the strong base sodium hydride, inTHF, to provide the amide anion which smoothly reacts with theelectrophilic methyl bromoacetate. Subsequent treatment of this esterproduct, still in THF, with aqueous sodium hydroxide gives the acid 2.Acid 2 can be coupled to the known aniline 3 (Bell, I. M., et al., PCTInt. Appl., WO 2004082605 A2 20040930) employing the standard peptidecoupling reagent combination of EDCI, HOAt and triethylamine, in DMF, toprovided the claimed compound 4. Analogs of lactam 1, if notcommercially available, can be prepared by a variety of common methods,one of which is illustrated in Scheme 2, for the preparation ofIntermediate 1.

Anhydride 5 can be converted to the bis-ester 6, though heating inmethanol, in the presence of HCl (generated from the reaction of TMSClwith MeOH). The less hindered ester of 6 can be selectively hydrolyzedwith potassium carbonate, in a mixture of THF, water and MeOH over thecourse of a few days. This acid can be converted in situ to thecorresponding acid chloride utilizing oxalyl chloride and a catalyticamount of DMF, in DCM, at ambient temperature. In the same reactionvessel, excess amine (or an amine hydrochloride-triethylamine mixture)can be introduced to give the amide 8. The amide 8 yields the ketone 9upon treatment with a Grignard reagent, or alternative organometallics,in THF at reduced temperatures. Alternatively, the pyrrolidinyl amideanalog of 8 can be of similar utility. Aryl ketone 9, can then betransformed into the sulfinamide 10 according to the one-pot procedureof Ellman and coworkers, Tetrahedron Lett., 1999, 40, 6709-6712.Treatment of 10 with anhydrous HCl in MeOH removes the t-butyl sulfinylgroup, and upon addition of sufficient triethylamine, producesIntermediate 1 (compound 11), where heating is employed as necessary.

Bromide 12 can react with the thiol carboxylic acid in the presence ofNaHCO₃ in a mixture of THF and water to produce the aryl ketone 13 atambient temperature. The carboxylic acid 13 can be converted to themethyl ester 14 through treatment with TMS diazomethane. Compound 14,can then be transformed into the sulfinamide 15 according to the one-potprocedure of Ellman and coworkers, Tetrahedron Lett., 1999, 40,6709-6712. Treatment of 15 with anhydrous HCl in MeOH removes thet-butyl sulfinyl group, and upon addition of sufficient triethylamine,produces Intermediate 2 (compound 16), under refluxing conditions.

Compound 17, prepared from 16 according to Scheme 1, can be oxidizedwith m-CPBA in chloroform at 0° C. to generate 18 as a mixture ofsulfoxides.

The aryl ketone 9 (from Scheme 2) can be transformed into thesulfinimine 19 utilizing Ti(OEt)₄ in THF at elevated temperatures. Thesulfinimine can then be treated with a Grignard reagent, or alternativeorganometallics, in THF at reduced temperatures to produce thesulfinamide 20. Treatment of 20 with anhydrous HCl in MeOH removes thet-butyl sulfinyl group, and upon addition of sufficient triethylamine,produces the lactam 21, under refluxing conditions in toluene. Lactam 21can be deprotonated with the strong base potassium hydride, in THF, toprovide the amide anion which smoothly reacts with methyl bromoacetate.Treatment of this ester product 22, in THF with potassiumtrimethylsilanolate gives the potassium carboxylate 23. Compound 23 canbe coupled to aniline 3 (Scheme 1), employing the standard peptidecoupling reagent combination of EDCI, HOAt and triethylamine, in DMF, toprovide the claimed compound 24.

Individual sulfoxides and sulfones can be accessed as shown in Scheme 6,where these carboxylic acids (28, 31 and 32) can be utilized in a mannersimilar to compound 2, Scheme 1. Compound 25 (prepared according toScheme 3) can be alkylated with benzyl bromoacetate in THF, subsequentto deprotonation with sodium hydride, to yield benzyl ester 26. Thesulfur of 26 can be oxidized to the sulfone 27 using mCPBA in DCM, atambient temperature. The benzyl ester of 27 can then be removed usingpalladium on carbon under an atmosphere of hydrogen to yield thecarboxylic acid 28. The sulfur of 26 can be oxidized to a mixture ofmajor and minor sulfoxides (29 and 30) using hydrogen peroxide, in anacidic mixture of water and methanol, at 40° C. This mixture ofsulfoxides can be separated into the individual epimers prior to removalof the benzyl ester using palladium on carbon under an atmosphere ofhydrogen to individually produce the carboxylic acids 31 and 32.

The synthesis of some heterocyclic amine intermediates may be conductedas described in Schemes 7-9. The methodology shown in these schemes isnot limited to the azaoxindoles shown but may be applied to a variety ofheterocyclic systems to give the corresponding spiro compounds. Relatedintermediates bearing a variety of substituents may be prepared byemploying appropriately substituted starting materials or byderivatization of any intermediates and/or final products as desired bymethods known in the art.

Scheme 7 illustrates a route to the 3-aminopyridine 41. 7-Azaindole (33)may be protected with a variety of protecting groups, such as the2-(trimethylsilyl)ethoxymethyl group shown in Scheme 7. Following themethod of Marfat and Carter [(1987) Tetrahedron Lett. 28, 4027],treatment of 34 with pyridine hydrobromide perbromide provides thedibromoazaoxindole 35, which may be reduced to the correspondingazaoxindole 36 by reaction with zinc. Bis-alkylation of the azaoxindole36 with 1,4-dibromobutan-2-one [de Meijere et al. (2001) Eur. J. Org.Chem. 3789] provides the cyclopentanone 37. Condensation of ketone 37with ammonia and 1-methyl-3,5-dinitropyridin-2(1H)-one [Tohda et al.(1990) Bull. Chem. Soc. Japan 63, 2820] in refluxing methanol leads tothe 3-nitropyridine derivative 39. Catalytic hydrogenation may be usedto provide the corresponding amine 40. Standard deprotection of 40 usingsequential acid and base treatments affords the 3-aminopyridineintermediate 41.

A representative synthesis of an isomer of compound 41, the2-aminopyridine 47, is shown in Scheme 8. The known pyridine diester 42[Hashimoto et al. (1997) Heterocycles 46, 581] may be reduced to thecorresponding diol 43 with lithium borohydride. This diol can beconverted to the dibromide 44 by reaction with phosphorus tribromide inTHF. The previously described azaoxindole [Marfat & Carter (1987)Tetrahedron Lett. 28, 4027] may be reacted with dibromide 44 usinglithium hydroxide in aqueous THF to afford the spiroazaoxindole 45. Avariety of other bases and solvents may be employed in this alkylationreaction, and use of a different alkylating agent than the dibromideshown here can lead to other products. Treatment of compound 45 withaqueous NaOH at reflux effects hydrolysis of the nitrile, affording thecarboxylate salt 46. This carboxylic acid salt may be subjected to knownCurtius rearrangement conditions to provide, after deprotection,aminopyridine 47.

A synthetic route to another isomer of compound 41, the 2-aminopyridine54, is shown in Scheme 9. The known pyridine N-oxide 48 [Niiyami et al.(2002) Bioorg. Med. Chem. Lett. 12, 3041] is reacted with trimethylsilylcyanide and dimethylcarbamoyl chloride in DME to give nitrile 49. Thisdiester may be reduced to the corresponding diol 50 with lithiumborohydride, and the diol can be converted to the dibromide 51 inanalogy with the chemistry described in Scheme 8. The protectedazaoxindole 36 may be reacted with dibromide 51 in DMF using cesiumcarbonate as base to afford the spiroazaoxindole 52. A variety of otherbases and solvents may be employed in this alkylation reaction, and useof a different alkylating agent than the dibromide shown here can leadto other products. Treatment of compound 52 with aqueous HCl at refluxeffects simultaneous hydrolysis of the nitrile and deprotection of theazaoxindole, affording the key acid intermediate 53. This carboxylicacid may be subjected to a similar Curtius rearrangement and subsequentdeprotection to that shown in Scheme 8 to afford the desiredaminopyridine 54.

Spiroazaoxindole intermediates, such as those illustrated in theseschemes (vide supra), may be resolved to give pure enantiomers usingtechniques familiar to those skilled in the art. For example,chromatography of the suitable intermediates on a chiral column can beused to provide the individual stereoisomers. Resolution may also beeffected by other methodologies, such as fractional crystallization ofdiastereomeric salts, and it may be carried out on other syntheticintermediates or on the final products. Alternatively, an asymmetricsynthesis of a key intermediate could be used to provide anenantiomerically enriched final product.

The synthesis of a number of piperidinone intermediates may be conductedas described in Schemes 10-12.

Scheme 10 illustrates a route to 6-substituted piperidin-2-ones, basedupon addition of a Grignard reagent (R′MgBr) to the tert-butylsulfinylimine 100, in analogy with methodology developed by Ellman and coworkers(Ellman et al., Acc. Chem. Res., 2002, 35, 984-995). After addition ofthe Grignard reagent, which usually proceeds with highdiastereoselectivity, the mixture may be heated to reflux to effectdeprotection of the resulting sulfinamide and cyclization to providepredominantly one enantiomer of the piperidinone 101. One modificationof these procedures involves use of an alternative organometallicreagent, such as an organolithium (R′Li), which may also be used toprovide lactam product 101 under similar conditions. The lactam 101 maybe alkylated with, for example, methyl bromoacetate (R″=Me) using sodiumhydride as base and the intermediate ester can be saponified in situusing sodium hydroxide to provide the desired carboxylic acid derivative102. In some cases, it is desirable to chromatograph intermediates suchas 102 using a chiral column in order to improve their enantiomericpurity.

An alternative route to piperidinones of general structure 102 is shownin Scheme 11. In this case, the organometallic reagent, such as anorganolithium (R′Li) is reacted with the Weinreb amide 103 to afford thecorresponding ketone 104. Reductive amination of 104 with glycine understandard conditions, followed by addition of xylenes and heating atreflux to effect cyclization of the intermediate amine, provides lactam102 as a racemate.

Scheme 12 shows a route to analogues of the piperidin-2-one 102 bearinghydroxy- or oxo-substituents at the 4-position. Starting from a3,3-disubstituted pyridine-2,4-dione (105), a substituent at the6-position may be introduced by addition of a Grignard reagent (R′MgBr)using published procedures (U.S. Pat. No. 2,525,231). The resultingketolactam 106 is subjected to borohydride reduction to afford thecorresponding alcohol 107 as a mixture of four stereoisomers. Standardalkylation methodology can then be applied to derivatize 107 with, forexample, ethyl bromoacetate and the resulting mixture may be separatedto afford the cis-isomer 108 and trans-isomer 109. These diastereomersmay also be resolved to provide the individual enantiomers of 108 and109 via chiral chromatography. Saponification of the ester 108 leads tothe key acid intermediate 110, and similar conditions may be used tosaponify 109. Alternatively, alcohol 108 may be subjected to oxidationwith Jones reagent to give ketone 111, which may be deprotected to theacid intermediate 112.

Scheme 13 shows a route to morpholinone intermediates. Addition of aGrignard reagent (R′MgBr) to sulfinimine 113 in THF proceeds withreasonable diastereoselectivity to provide sulfinamide 114 as describedin the literature (Barrow et al., Tetrahedron Lett., 2001, 42,2051-2054). After purification and deprotection, the (R)-glycinolderivative 115 may be obtained. There are numerous other syntheticroutes for the synthesis of 115, as described in the literature, andthese may be employed as alternatives to the route illustrated herein.Elaboration of 115 to give the protected morpholinone 119 may be carriedout in analogy with published methodology (Anthony et al., TetrahedronLett., 1995, 36, 3821-3824). Essentially, treatment of 115 withchloroacetyl chloride, followed by sodium hydride, provides morpholinone116, which may be protected to give 117. Treatment of 117 with sodiumbis(trimethylsilyl)amide followed by iodomethane provides thetrans-substituted morpholinone 118, and retreatment with base followedby iodomethane leads to the dimethyl analogue 119. Standard removal ofthe Boc group is effected using trifluoroacetic acid to give 120, whichmay be converted to the acetate derivative 121 in analogy with previousschemes. It is understood by those skilled in the art of organicsynthesis that simple modifications of this route may give rise to othercompounds of interest. For example, the monomethyl derivative 118 may bedeprotected and alkylated using similar conditions as those used toelaborate 119, to provide the corresponding (2S,5R)-2-methylmorpholinoneanalogue. Alternatively, other alkylating agents may be used in place ofiodomethane, such as iodoethane or benzyl bromide, to provide a varietyof morpholinone derivatives.

In Scheme 14, the synthesis of the cis-substituted morpholinoneintermediate 123 is outlined. In this case, reaction of glycinol 115with 2-chloropropionyl chloride, followed by treatment with sodiumhydride, leads selectively to the (2R,5R)-2-methylmorpholinone 122,which may be elaborated to the acid intermediate 123 using standardprocedures. A combination of the methodology illustrated in the twoprevious schemes may also be employed to provide intermediates ofinterest, as shown in Scheme 15.

Following the initial procedures in Scheme 14, but using 2-chlorobutyrylchloride for the acylation, leads to the 3-ethylmorpholinone derivative124. This morpholinone intermediate may be elaborated in analogy withmorpholinone 116 in Scheme 13. Instead of sequential dialkylation withiodomethane, a monoalkylation procedure is performed using iodoethane asthe electrophile to afford the diethylmorpholinone 126, which may beconverted to the key acid intermediate 128 as shown.

Scheme 16 illustrates methodology for synthesis of piperazinoneintermediates, such as 133 and 135. Alkylation of an α-aminoester withbromide 129 may be used to provide the aminoketone 130. A variety ofbases, including NaHCO₃, K₂CO₃, and Na₃PO₄ may be utilized in thisalkylation reaction. The aminoketone product may be subjected toreductive amination with ammonium acetate to give the correspondingdiamine, which usually undergoes cyclization in situ to providepiperazinone 131. Protection of 131 as the tert-butyl carbamate,followed by alkylation with ethyl bromoacetate, leads to the ester 132as shown and saponification provides the corresponding acid 133. Analternative strategy is reductive amination of aminoketone 130 with, forexample, glycine ethyl ester as shown in Scheme 16. Under the acidicconditions of the reaction, the initial diester intermediate cyclizes togive piperazinone 134, which may be saponified to give acid 135. Simplemodifications of the routes illustrated in Scheme 16 may be used toprovide other piperazinone intermediates of interest. For example,addition of formaldehyde to the reductive amination reaction oncepiperazinone 134 is produced can lead to a rapid methylation reaction,affording the N-Me analogue of compound 134. Other standardderivatizations of the piperazinone ring, including alkylation,acylation, or sulfonylation, may be applied to intermediates like 134 orto the final amide products to provide analogues of interest. In somecases, use of known protecting group strategies may be usefully applied.For example, protection of piperazinone 134 with a tert-butyl carbamategroup would provide compound 132 and this may facilitate subsequentpurification and synthesis. In Scheme 16, the intermediates 131-135 areobtained as mixtures of stereoisomers, but straightforward techniques,such as chiral chromatography, may be applied to such intermediates toeffect separation of these isomers.

Simple modifications of these routes, including different protectinggroup strategies, application of well-precedented methodology, and theuse of starting materials and reagents other than those described in theforegoing schemes, may be used to provide other acids of interest

Intermediates, such as those described above, may be converted to avariety of other key intermediates that are useful in the synthesis ofthe compounds of the present invention. While the methodology shown inScheme 1 is exemplified using lactam 1, it is understood that it may beapplied to a variety of lactam substrates, such as those describedherein, in order to provide various compounds of the present invention.For example, Scheme 17 illustrates the synthesis of claimed compoundsthat are analogous to those in Scheme 1 but of a more general structure.A lactam of general structure 136, may be alkylated with an electrophileof general formula BrR^(e)R^(f)CCO₂Me after deprotonation with asuitable base, such as sodium hydride, in an appropriate solvent, suchas THF. The ester, although not limited to methyl ester, may then behydrolyzed by an appropriate base, such as NaOH, to provide acid 137.Acid 137 may then be coupled to aniline 138 using a variety of peptidecoupling reagent combinations, such as EDCI and HOAt, in the presence ofan appropriate base, such as triethylamine, in an appropriate solvent,such as DMF, to yield compound 139.

It is understood by those skilled in the art that in some casesalternative reagents or conditions may be used to effect thetransformations in Scheme 17. The exact choice of reagents, solvents,temperatures, and other reaction conditions, depends upon the nature ofthe intended product. In some cases, additional chemical steps may berequired to obtain the compounds of interest, or various protectinggroup strategies may be employed.

The lactam intermediates, such as 1, may be obtained from commercialsources or prepared according to Scheme 2, such as 11. While themethodology shown in Scheme 2 is exemplified using anhydride 5, it isunderstood that it may be applied to a variety of substrates, such asthose described herein, in order to provide various lactamintermediates. For example, Scheme 18 illustrates the synthesis of keyintermediates that are analogous to those in Scheme 2 but of a moregeneral structure.

Anhydrides of general structure 140 can be converted to a number ofbis-esters analogous to 141, using an appropriate alcohol, such as MeOH,and an acid catalyst, such as HCl. Selective deprotection of one estermay be accomplished using a mild base, such as K₂CO₃, in an appropriatesolvent mixture, to provide acid 142. Acid 142, may then be coupled withan appropriate amine, such as methylmethoxyamine or pyrrolidine, usingan appropriate amide-forming reagent combination, such as oxalylchloride and catalytic DMF, to provide an amide, such as 143, inpreparation for ketone formation. A variety of organometallic reagents,such as BrMgR¹¹, may then be allowed to react with 143, to provideketone 144. Conversion of ketone 144 to sulfinamide 145 may be achievedusing a variety of known methodology, [see, for example Ellman et al.(1987) Tetrahedron Lett. 40, 6709-6712]. Conversion of compound 145 intokey lactam intermediate 146 may be achieved using an appropriate acid,such as HCl, followed by an appropriate base, such as triethylamine toallow spontaneous lactamization in an appropriate solvent, such as MeOH,at a temperature ranging from 0-150° C. It is understood thatalternative methodologies may also be employed in the synthesis of thesekey intermediates. For instance, racemic reaction sequences may beutilized, followed by chiral separations at appropriate steps to providecompounds of the present invention. The exact choice of reagents,solvents, temperatures, and other reaction conditions, depends upon thenature of the intended product. In some cases, appropriate protectinggroup strategies may be used.

Alpha-halo ketones 147, can react with various alpha-thio carboxylicacids (HS(R⁶)(R⁷)CCO₂H), in the presence of an appropriate base, such asNaHCO₃, in a mixture of solvents, such as THF/water to give thecarboxylic acid 148. This carboxylic acid may be converted to the ester149 under a variety of conditions, such as TMS diazomethane in anappropriate solvent, such as methanol. Alternatively, alpha-halo ketones147, may react with various alpha-thio carboxylic acid esters(HS(R⁶)(R⁷)CCO₂Me), to provide 149 directly. Conversion of ketone 149 tosulfinamide 150 may be achieved using a variety of known methodology,such as Ellman et al. (1987) Tetrahedron Lett. 40, 6709-6712. Conversionof compound 150 into key lactam intermediate 151 may be achieved usingan appropriate acid, such as HCl, followed by an appropriate base, suchas triethylamine to allow spontaneous lactamization in an appropriatesolvent, such as toluene, at a temperature ranging from 0-150° C.Compound 151 may be elaborated in an analogous manner as compound 1 toprovide claimed compounds.

Thioether of general formula 152, may be oxidized with an appropriateoxidant, such as mCPBA or hydrogen peroxide, in an appropriate solvent,such as DCM or a mixture of an alcohol and water, at a temperatureranging from 0-150° C., to give sulfur-oxidized compounds 153.

Alternatively, amide of general structure 154, may be alkylated with anelectrophile of general formula BrR^(e)R^(f)CCO₂Me after deprotonationwith a suitable base, such as potassium hydride, in an appropriatesolvent, such as THF to provide 155. Oxidation of 155 with an oxidant,such as mCPBA, in an appropriate solvent, such as DCM, provides thesulfone 156. The benzyl ester of 156 can then be cleaved using a metalcatalyst, such as palladium on carbon, under an atmosphere of hydrogen,or other reducing conditions, to yield the carboxylic acid 157.Sulfoxide 158, may be obtained from compound 155, by employingalternative oxidation conditions, such as aqueous hydrogen peroxide, inan appropriate co-solvent, such as MeOH, under acidic conditions, andover a temperature range of 0-150° C. The benzyl ester of 158 can thenbe cleaved using a metal catalyst, such as palladium on carbon, under anatmosphere of hydrogen, or other reducing conditions, to yield thecarboxylic acid 159. Compounds 157 and 159 may be elaborated in ananalogous manner as compound 2 to provide claimed compounds.

Ketone 144 (Scheme 18) may be converted to the sulfinimine 160 utilizingan appropriate dehydration reagent, such as titanium tetraethoxide, in asolvent, such at THF, in a temperature range of 20-150° C. Treating 160with an appropriate organometallic reagent, such as R¹⁰MgBr, in anaprotic solvent, such as DCM, at a temperature between −78 and 25° C.yields compound 161. Conversion of compound 161 into key lactamintermediate 162 may be achieved using an appropriate acid, such as HCl,followed by an appropriate base, such as triethylamine to allowlactamization in an appropriate solvent, such as MeOH or toluene, at atemperature ranging from 0-150° C. Lactam of general structure 162, maybe alkylated with an electrophile of general formula BrH₂CCO₂Me afterdeprotonation with a suitable base, such as potassium hydride, in anappropriate solvent, such as THF to provide 163. Dealkylation of themethyl ester in 163, may be effected using KOTMS in an appropriatesolvent, such as THF, in a temperature range of 0 to 40° C., to providethe potassium carboxylate 164. Alternatively, hydrolysis may be achievedunder a variety of basic or acidic conditions. Compound 164 may beelaborated in an analogous manner as compound 2 to provide claimedcompounds.

The amine of beta-amino acid esters of general formula 165, although notlimited to ethyl esters, may be protected as their N-Boc derivativesusing standard conditions such as Boc-anhydride, a base, such astriethylamine, in an appropriate solvent, such as DCM, to provide ester166. This ester may be reduced to the corresponding aldehyde 167 using areductant, such as diisobutylaluminum hydride, in an appropriatesolvent, such as DCM, at a temperature between −78° C. and rt.Ester-protected amino acids of general formula 168, although not limitedto methyl esters, may then be reductively alkylated with aldehyde 167using a reducing reagent, such as NaHB(OAc)₃, a base as needed, such asHunig's base, in a solvent, such as chloroform, at a temperature rangingfrom −30 to 100° C., to provide 169. The amine protecting group of 169may then be removed under standard conditions using a strong acid suchas hydrogen chloride, in an appropriate solvent, such as MeOH, toprovide 170. The coupling of fragments 170 and 171 may be affected byfirst allowing the aryl amine of 171 to react with an appropriateacylating reagent, such as bromoacetyl bromide, in the presence ofexcess base, such as triethylamine, in an aprotic solvent, such as THF,at a temperature between 0° C. and rt, for an appropriate length oftime, after which 170 and additional base may be added prior to anincrease in the reaction temperature to the range of 30-70° C.,ultimately providing 172. The ester of 172, although not limited tomethyl ester, may then be deported to the corresponding acid orcarboxylate salt 173 using an appropriate reagent, such as KOTMS, in asolvent such as THF over a temperature range of −20 to 60° C. Thepotassium carboxylate salt 173, or the corresponding carboxylic acid,may then be cyclized using a variety of peptide-coupling reagentcombinations, such as EDCI and HOAt, in the presence of an appropriatebase (as needed), such as triethylamine, in an appropriate solvent, suchas DMF, to yield compound 174.

Alternatively, as shown in Scheme 24, compound 170 from Scheme 23 may becyclized to 175 by first deprotection of the ester with a suitablereagent, such as KOTMS, in an appropriate solvent, such as THF.Subsequent to the cleavage of the ester, the pH of the solution may beadjusted to approximately pH=8, by the addition of an aqueous acid, suchas 1 M HCl, followed by addition of an appropriate peptide couplingreagent combination, such as EDCI and HOAt, to provide 175. The amidenitrogen of 175 may then be alkylated by the addition of a strong base,such as NaH, in an appropriate solvent, such as THF, followed by theaddition of an appropriate alkylating reagent 176, such as benzylbromoacetate, to provide 177. The ester of 177 may be converted to theacid under reducing conditions, such as Pd/C in the presence ofhydrogen, or alternatively aqueous hydrolysis methods, to provide acid178. Acid 178 may then be coupled to aryl amine 171 using a variety ofpeptide coupling reagent combinations, such as EDCI and HOAt, in thepresence of an appropriate base, such as triethylamine, in anappropriate solvent, such as THF, to yield compound 179.

In Scheme 25, an alternative strategy for the synthesis of piperazinoneintermediates is illustrated. This methodology is useful for thesynthesis of examples for which R¹⁰ is not hydrogen. This route beginswith the protected amino ester 180, which may be synthesized via anumber of routes that are known in the chemical literature. In thisillustrative case, a tert-butyl carbamate protecting group is shown on180, but other protecting group strategies may be equally effective.Reduction of the ester group in 180, using LiAlH₄ or an alternativereducing agent, may provide the corresponding aldehyde 181 directly,depending upon the nature of R, R¹⁰, and R¹¹. In some cases, it may beadvantageous or necessary to access aldehyde 181 via a two-stepprocedure in which the ester is reduced to the corresponding alcohol andthe alcohol is oxidized to afford aldehyde 181 using, for example, Swernconditions. Reductive amination of 181 with a suitable amino ester understandard conditions can be used to provide the amine 182, and this maybe deprotected and cyclized under acidic conditions to give piperazinone183. Piperazinone 183 may be further elaborated in analogy with Scheme16 to give key acid intermediates like 186. In Scheme 25, theintermediates 183-186 are obtained as mixtures of stereoisomers, butstraightforward techniques, such as chiral chromatography, may beapplied to such intermediates to effect separation of these isomers.

The various carboxylic acid intermediates described in these schemes(vide supra) may be coupled to a variety of amines to give the compoundsof the present invention. A general reaction is illustrated in Scheme26, in which carboxylic acid A is coupled to amine B to give the desiredproduct amide C. There are many known strategies for effecting suchcoupling chemistry, including use of coupling reagents, such as EDC withHOBT, PyBOP, HATU, CDI and the like. Alternatively, the carboxylic acidA may be activated as an acid chloride or anhydride, for example, tofacilitate reaction with the amine of interest. Activation of the amineB, for example as the corresponding aluminum amide which may be reactedwith an ester derivative of carboxylic acid A, may also be a usefulstrategy in cases where the amine is relatively unreactive. In somecases, various protecting group strategies familiar to one skilled inthe art of organic synthesis may be employed to allow preparation of aparticular compound of the present invention.

It is understood that alternative methodologies may also be employed inthe synthesis of these key intermediates. For instance, racemic reactionsequences may be utilized, followed by chiral separations at appropriatesteps to provide compounds of the present invention. The exact choice ofreagents, solvents, temperatures, and other reaction conditions, dependsupon the nature of the intended product. In some cases, appropriateprotecting group strategies may be used.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. Additionally, various protecting group strategies may beemployed to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

(6S)-6-(3,5-Difluorophenyl)-3,3-dimethylpiperidin-2-one Step A. Dimethyl2,2-dimethylpentanedioate

To a solution of 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione (20.0 g, 141mmol) in MeOH (140 mL), at ambient temperature and under a constantstream of nitrogen, was added TMSCl (7.64 g, 70.3 mmol). The reactionmixture was then heated to 60° C. for 3.25 h, before being cooled toambient temperature. The reaction mixture was then concentrated in vacuobefore being diluted with diethyl ether (200 mL) and water (100 mL). Theorganics were then washed with 100 mL, individually, of each of thefollowing aqueous solutions: 1 M NaOH, 1 M HCl, water, half-saturatedbrine and saturated brine. The organics were then dried over sodiumsulfate, filtered and concentrated in vacuo to give the title compound,which was used without further purification. MS: m/z=189 (M+1).

Step B. 5-Methoxy-4,4-dimethyl-5-oxopentanoic acid

To a solution of dimethyl 2,2-dimethylpentanedioate from Step A (25.4 g,135 mol) in MeOH (150 mL), THF (100 mL) and water (100 mL), was addedpotassium carbonate (36.2 g, 262 mmol). This biphasic solution wasallowed to stir for 68 h, at ambient temperature, after which time thereaction was about 50% complete. Solvents were carefully removed invacuo such that the starting materials did not vaporize. The aqueouslayer was diluted with water (266 mL) and then extracted with diethylether until no additional SM was detected in the aqueous layer. Theaqueous layer was made acidic by the addition of 6 M HCl (95 mL), andwas then saturated with NaCl. This aqueous layer was extracted once withdiethyl ether (250 mL). This ethereal layer was washed with brine, thendried over sodium sulfate, filtered and concentrated in vacuo to givethe title compound. MS: m/z=175 (M+1).

Step C. Methyl 5-[methoxy(methyl)amino]-2,2-dimethyl-5-oxopentanoate

To a solution of 5-methoxy-4,4-dimethyl-5-oxopentanoic acid from Step B(7.00 g, 40.2 mmol), in DCM, was added DMF (0.1 mL), followed by theslow addition of oxalyl chloride (5.00 g, 39.4 mmol) over 33 minutes,during which time the reaction flask was maintained under a constantstream of dry nitrogen. Stirring was continued under a light stream ofdry nitrogen for an additional hour, during which time the rate ofcarbon dioxide evolution diminished. This freshly formed acid chloridewas then transferred via cannula into a 500 mL round bottom flask,cooled to 0° C., which already contained N-methoxymethanaminehydrochloride (5.76 g, 59.1 mmol) and triethylamine (15.9 g, 158 mmol).Fifteen minutes after complete addition of the acid chloride, the icebath was removed and the reaction was allowed to warm to ambienttemperature. After 1 h at ambient temperature, diethyl ether (100 mL)was added to precipitate some of the triethylamine hydrochloride, whichwas filtered and washed with more diethyl ether. The combined organicswere then washed with 1M HCl (100 mL×2), 1M NaOH (100 mL), water (100mL), half-saturated brine (100 mL) and saturated brine (100 mL). Theorganics were then dried over sodium sulfate, filtered and concentratedin vacuo to provide the title compound which was used without furtherpurification. MS: m/z=218 (M+1).

Step D. Methyl 5-(3,5-difluorophenyl)-2,2-dimethyl-5-oxopentanoate

To a solution of methyl5-[methoxy(methyl)amino]-2,2-dimethyl-5-oxopentanoate from Step C (4.68g, 21.6 mmol) in THF (46.8 mL), cooled to 0° C., was added3,5-difluorophenyl magnesium bromide (65 mL, 0.5 M in THF, 32.3 mmol)over 30 minutes. The reaction was allowed to stir at ambient temperaturefor 2 h, after which time no additional reaction progress was observed.Additional 3,5-difluorophenyl magnesium bromide (50 mL, 0.5 M in THF,25.0 mmol) was added over 30 minutes. After 3 h at 0° C., the reactionwas quenched by the rapid addition of a cold (0° C.) solution of EtOH(71 mL) and cone. HCl (5.0 mL). The reaction was then diluted with water(200 mL) and diethyl ether (400 mL). The organics were washed with water(200 mL×3) and brine (100 mL), then dried over sodium sulfate, filtered,and concentrated in vacuo to give a residue. This residue was purifiedby silica gel chromatography, eluting with a gradient ofCH₂Cl₂:hexanes—50:50 to 100:0, to give the title compound. MS: m/z=239(M−31(MeO⁻)).

Step E. Methyl(5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate

To a solution of methyl5-(3,5-difluorophenyl)-2,2-dimethyl-5-oxopentanoate from Step D (500.mg, 1.85 mmol) and (S)-2-methylpropane-2-sulfinamide (336 mg, 2.78 mmol)in THF (6.5 mL), was added titanium tetraethoxide (616 mg, 2.52 mmol).The reaction vessel was quickly sealed and placed into a 60° C. bath for3 hours. After cooling to ambient temperature a septum and nitrogeninlet were attached prior to cooling to 0° C. Sodium borohydride (191mg, 5.05 mmol) was then added, and a complete reaction was observedafter 15 minutes. Methyl alcohol was then slowly added until gasevolution had stopped. The reaction mixture was then diluted withsaturated brine (6.5 mL) while experiencing rapid stirring. Theresultant slurry was filtered through celite, washing with EtOAc asneeded. The combined organics were then washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo to give an oil. Thisoil was purified by silica gel chromatography, eluting with a gradientof EtOAc:Hexanes—10:90 to 70:30, to give the title compound containingabout 12% of the corresponding ethyl ester. MS: m/z=376 (M+1).

Step F. (6S)-6-(3,5-Difluorophenyl)-3,3-dimethylpiperidin-2-one

A solution of methyl(5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)-2,2-dimethylpentanoatefrom Step E (300. mg, 0.800 mmol) in MeOH (16 mL) was cooled to 0° C.Hydrogen chloride gas (anhydrous) was bubbled through this cold solutionfor about 30 seconds, after which time the reaction vessel was sealedand allowed to sit in the ice bath for 15 minutes. Dry nitrogen was thenbubbled through the solution for 30 minutes, prior to removal of solventin vacuo. More MeOH (˜50 mL) was added, and then removed in vacuo. Afterdissolving in a third volume of MeOH (16 mL), triethylamine (323 mg, 3.2mmol) was introduced and the mixture was heated to 65° C. for 16 hours.After cooling to ambient temperature, the solvent was removed in vacuoand the residue was partitioned between diethyl ether (50 mL) and 1 MHCl (50 mL). The organics were washed with additional 1 M HCl (50 mL),water (50 mL) and saturated brine (50 mL). The ethereal solution wasdried over sodium sulfate, filtered and then concentrated in vacuo toprovide the title compound, which could be used without furtherpurification. MS: m/z=240 (M+1).

(5R)-5-(3,5-Difluorophenyl)-2,2-dimethylthiomorpholin-3-one Step A.2-{[2-(3,5-Difluorophenyl)-2-oxoethyl]thio}-2-methylpropanoic acid

To a solution of 3,5-difluorophenacyl bromide (845 mg, 3.60 mmol) in THF(12 mL) and water (12 mL) was added sodium bicarbonate (317 mg, 3.78mmol) and 2-mercaptoisobutryic acid (432 mg, 3.60 mmol). The reactionmixture was allowed to stir at ambient temperature for 1.0 h under astream of nitrogen. The reaction mixture was diluted with diethyl ether(50 mL) and 1 M HCl (15 mL). The organic layer was then washed with 20mL saturated brine. The organics were then dried over sodium sulfate,filtered and concentrated in vacuo to give the title compound, which wasused without further purification. MS: m/z=229 (M−CO₂H).

Step B. Methyl2-{[2-(3,5-difluorophenyl)-2-oxoethyl]thio}-2-methylpropanoate

To a solution of2-{[2-(3,5-difluorophenyl)-2-oxoethyl]thio}-2-methylpropanoic acid fromStep A (400. mg, 1.46 mmol) in MeOH (3 mL), was addedtrimethylsilyldiazomethane (2 M in hexanes) until yellow color persists.The reaction mixture was stirred for an additional twenty minutes. Thereaction mixture was diluted with ether (30 mL) and water (10 mL). Theorganics were washed with 5% sodium bicarbonate and then with saturatedbrine. The organics were dried over sodium sulfate, filtered, andconcentrated in vacuo to give a residue. This residue was purified bysilica gel chromatography, eluting with a gradient ofCH₂Cl₂:Hexanes—40:60 to 90:10, to give the title compound. MS: m/z=229(M−CO₂Me).

Step C. Ethyl2-{[(2R)-2-[(tert-butylsulfinyl)amino]-2-(3,5-difluorophenyl)ethyl]thio}-2-methylpropanoate

To methyl 2-{[2-(3,5-difluorophenyl)-2-oxoethyl]thio}-2-methylpropanoatefrom Step B (500. mg, 1.74 mmol) was added(R)-(+)-2-methyl-2-propanesulfinamide (254 mg, 2.09 mmol) under aconstant stream of nitrogen. The reagents were dissolved in THF (17 mL),and to the above mixture was added titanium ethoxide (796 mg, 3.49mmol). The reaction was sealed and stirred at 60° C. for 15 hours. Thereaction was complete as determined by LCMS analysis andtransesterification was observed. The reaction was cooled gradually to0° C. under nitrogen. To the reaction mixture was added sodiumborohydride (132 mg, 3.49 mmol). The reaction was complete after fifteenminutes as indicated by LCMS analysis. The reaction was quenched afteran additional twenty minutes of stirring with methanol until gasevolution ceased. Saturated brine (30 mL) was added with heavy stirringand the resulting slurry was filtered through celite and washed withaliquots of ethyl acetate. The organic layer was then washed with brineand dried over sodium sulfate. The solution was filtered andconcentrated in vacuo to provide a residue that was purified by silicagel chromatography, eluting with a gradient of EtOAc:Hexanes—20:80 to75:25, to give the title compound (containing 10% of the undesireddiastereomer). MS: m/z=408 (M+1).

Step D. (5R)-5-(3,5-Difluorophenyl)-2,2-dimethylthiomorpholin-3-one

To a solution of methyl2-{[(2R)-2-[(tert-butylsulfinyl)amino]-2-(3,5-difluorophenyl)ethyl]thio}-2-methylpropanoatefrom Step C (428 mg, 1.09 mmol) in MeOH (20 mL), cooled to 0° C., wasadded anhydrous HCl gas for 1 minute. The reaction was sealed andallowed to sit at 0° C. for fifteen minutes, after which nitrogen wasbubbled through the reaction for twenty minutes. The reaction wasconcentrated in vacuo. Additional MeOH (30 mL) was added and it wasagain concentrated in vacuo. This was repeated with another addition ofMeOH and triethylamine (440. mg, 4.35 mmol). To the resulting residuewas added toluene (10 mL) and triethylamine (440. mg, 4.35 mmol). Areflux condenser was attached and the mixture stirred at 115° C. Afterone week of stirring, the reaction was judged to be 90% complete byLCMS. The mixture was cooled to ambient temperature and concentrated invacuo. The residue was diluted with diethyl ether (50 mL) and washedindividually with 20 mL of each of the following aqueous solutions: 1 MHCl (twice), water, and saturated brine. The organic layer was thendried over sodium sulfate, filtered, and concentrated in vacuo to give aresidue that was purified by silica gel chromatography, eluting with agradient of MeOH:CH₂Cl₂—1:99 to 5:95, to give the title compound. MS:m/z=258 (M+1).

Benzyl 5-{[(S)-tert-butylsulfinyl]imino}-2,2-dimethylpentanoate Step A.Benzyl 2,2-dimethylpent-4-enoate

To a mixture of K₂CO₃ (1.58 g, 11.5 mmol), 2,2-dimethylpent-4-enoic acid(1.30 g, 10.1 mmol) and DMF (8.1 mL) was added benzyl bromide (1.40 g,8.19 mmol) slowly over 15 minutes. After 4 hours the mixture was dilutedwith a mixture of water (80 mL) and diethylether (80 mL). The organiclayer was separated and sequentially washed with 80 mL of 5% aqueoussodium bicarbonate, saturated copper sulfate, slightly acidic water,half-saturated brine, and then saturated brine. The organics were thendried over sodium sulfate, filtered and concentrated in vacuo to givethe title compound which was used without further purification. MS:m/z=219 (M+1).

Step B. Benzyl 5-hydroxy-2,2-dimethylpentanoate

To a solution of benzyl 2,2-dimethylpent-4-enoate (5.74 g, 26.3 mmol,prepared according to Step A) in THF (100 mL) was added a solution of9-BBN (63.1 mL, 31.6 mmol, 0.5 M in THF) over 20 minutes, while undernitrogen. The reaction was allowed to stir at ambient temperature for 17hours. An aqueous solution of sodium acetate (7.3 g, 89 mmol, in 18 mLof water) was then added, followed by the slow addition of aqueoushydrogen peroxide (18 mL, 30% by weight solution) with occasionalchilling in a 0° C. bath. This mixture was allowed to stir at ambienttemperature for 1.5 hours, before being extracted with ethyl acetate.The combined organics were washed with saturated brine. The organicswere then dried over sodium sulfate, filtered, and concentrated in vacuoto give a residue that was purified by silica gel chromatography,eluting with a gradient of MeOH:DCM—1:99 to 10:90, to give the titlecompound. MS: m/z=237 (M+1).

Step C. Benzyl 2,2-dimethyl-5-oxopentanoate

To a −78° C. solution of oxalyl chloride (4.80 g, 37.8 mmol) in DCM (200mL) was add DMSO (5.91 g, 75.6 mmol) dropwise over 10 minutes. After 25minutes of additional stirring, a −78° C. solution of benzyl5-hydroxy-2,2-dimethylpentanoate (4.06 g, 17.2 mmol, Step B) in DCM (200mL) was added via cannula over 75 minutes. After stirring for anadditional 30 minutes, triethylamine (13.9 g, 137 mmol) was added slowlyover 25 minutes. The cooling bath was allowed to warm, while thereaction stirred for an additional 18 hours. Reaction solvent was thenremoved in vacuo, and the residue was dissolved in a mixture of diethylether and water (containing enough HCl to remain acidic). The organicswere then dried over sodium sulfated, filtered and concentrated in vacuoto give the title compound (3.67 g), which was used without furtherpurification.

Step D. Benzyl 5-{[(S)-tert-butylsulfinyl]imino}-2,2-dimethylpentanoate

To a mixture of benzyl 2,2-dimethyl-5-oxopentanoate (1.06 g, 4.54 mmol,Step C) and anhydrous CuSO₄ (1.59 g, 9.98 mmol) in DCM (10 mL) was added(S)-2-methylpropane-2-sulfinamide (0.550 g, 4.54 mmol). This mixture wasstirred for 22 hours, before being filtered through a pad of celite.Additional DCM was used to wash the celite. The combined organics wereconcentrated in vacuo to give a residue that was purified by silica gelchromatography, eluting with a gradient of MeOH:DCM—0.5:99.5 to1.5:98.5, to give the title compound. MS: m/z=338 (M+1).

[(3R)-3-(3,5-Difluorophenyl)-1-oxido-5-oxothiomorpholin-4-yl]acetic acid(major sulfoxide isomer) Step A. Benzyl[(3R)-3-(3,5-difluorophenyl)-5-oxothiomorpholin-4-yl]acetate

To a 0° C. solution of (5R)-5-(3,5-difluorophenyl)thiomorpholin-3-one(247 mg, 1.08 mmol, prepared by analogy to Intermediate 2) in THF (8.0mL) was added sodium hydride (38 mg, 1.5 mmol, 95% by weight). After 5minutes, the ice bath was removed and the reaction was allowed to warmto ambient temperature. Once hydrogen gas evolution had ceased, asjudged by an oil bubbler, the reaction mixture was cooled to 0° C.,prior to the introduction of benzyl acetate (272 mg, 1.19 mmol). After 5minutes, the ice bath was removed and the reaction was stirred for 15hours. The bulk of the THF was removed under reduced pressure. Theresidue was then diluted with water and ether. The aqueous layer wasextracted once with ether and the combined organics were washed withsaturated brine. The organics were then dried over sodium sulfate,filtered, and concentrated in vacuo to give a residue that was purifiedby silica gel chromatography, eluting with a gradient ofMeOH:DCM—0.5:99.5 to 5:95, to give the title compound. MS: m/z=378(M+1).

Step B. Benzyl[(3R)-3-(3,5-difluorophenyl)-1-oxido-5-oxothiomorpholin-4-yl]acetate

To a solution of benzyl[(3R)-3-(3,5-difluorophenyl)-5-oxothiomorpholin-4-yl]acetate (151 mg,0.399 mmol, from Step A.) in MeOH (10 mL) was added aqueous hydrogenperoxide (30 drops, ˜0.8 mL, 30% by weight), and aqueous HCl (5 drops, 3M HCl). This mixture was then heated to 40° C. for 2.5 hours. Aftercooling to ambient temperature, the bulk of the MeOH was removed invacuo, and the residue was partitioned between 50 mL of water and 100 mLof diethyl ether. The organics were washed with saturated brine, thendried over sodium sulfate, filtered, and concentrated in vacuo to give aresidue that was purified by silica gel chromatography eluting with agradient of Hexanes:EtOAc—1:1 to 100% EtOAc, to yield 24.5 mg of theminor sulfoxide isomer and 93.6 mg of the major sulfoxide isomer. MS:m/z=394 (M+1).

Step C.[(3R)-3-(3,5-Difluorophenyl)-1-oxido-5-oxothiomorpholin-4-yl]acetic acid(major sulfoxide isomer)

A solution of benzyl[(3R)-3-(3,5-difluorophenyl)-1-oxido-5-oxothiomorpholin-4-yl]acetate(93.6 mg, 0.238 mmol, major isomer, from Step B) in MeOH (5 mL) waspurged with nitrogen. The septum sealing the reaction vessel was brieflyremoved to allow introduction of Pd/C (˜18 mg, 10% Pd/C). The vessel wasthen purged with hydrogen from a balloon, before a fresh balloon ofhydrogen was attached. After LCMS analysis indicated that the reactionhad stalled at 60% conversion, the hydrogen atmosphere was replaced withnitrogen. The mixture was then filtered through a pad of celite, washingwith MeOH as needed. The filtrate was concentrated in vacuo to provide aresidue which was diluted with aqueous sodium bicarbonate (2%) andether. The aqueous layer was extracted with ether (4 times) to removeun-reacted starting material. The aqueous layer was then made acidic bythe addition of 3M HCl, and was then saturated with NaCl. This acidicaqueous layer was then extracted three times with DCM and three timeswith EtOAc. Both organics were dried over sodium sulfate, filtered andconcentrated in vacuo to give the title compound. MS: m/z=304 (M+1).

[(3R)-3-(3,5-Difluorophenyl)-1-oxido-5-oxothiomorpholin-4-yl]acetic acid(minor sulfoxide isomer)

A solution of benzyl[(3R)-3-(3,5-difluorophenyl)-1-oxido-5-oxothiomorpholin-4-yl]acetate(24.5 mg, 0.062 mmol, minor isomer, from the preparation of Intermediate4, Step B) in MeOH (2 mL) was purged with nitrogen. The septum sealingthe reaction vessel was briefly removed to allow introduction of Pd/C(˜6 mg, 10% Pd/C). The vessel was then purged with hydrogen from aballoon, before a fresh balloon of hydrogen was attached. After LCMSanalysis indicated that the reaction was progressing slowly, asuspension of 10% Pd/C was introduced via syringe. After 2.25 hours thehydrogen atmosphere was replaced with nitrogen. The mixture was thenfiltered through a pad of celite, washing with MeOH as needed. Thefiltrate was concentrated in vacuo to provide the title compound, whichwas used without further purification. MS: m/z=304 (M+1).

[(3R)-3-(3,5-Difluorophenyl)-1,1-dioxido-5-oxothiomorpholin-4-yl]aceticacid Step A. Benzyl[(3R)-3-(3,5-difluorophenyl)-1,1-dioxido-5-oxothiomorpholin-4-yl]acetate

To a solution of benzyl[(3R)-3-(3,5-difluorophenyl)-5-oxothiomorpholin-4-yl]acetate (65.9 mg,0.175 mmol, from the preparation of Intermediate 4, Step A) in DCM (3mL) was added m-CPBA (86.0 mg, 0.350 mmol, 70% by weight). Afterstirring for 17 hours at ambient temperature, the reaction mixture wasapplied to a silica gel column for purification, eluting with a gradientof Hexanes:EtOAc—95:5 to 50:50, to give the title compound, which is 83%pure (balance being m-CPBA), and was used without further purification.

Step B.[(3R)-3-(3,5-Difluorophenyl)-1,1-dioxido-5-oxothiomorpholin-4-yl]aceticacid

A solution of benzyl[(3R)-3-(3,5-difluorophenyl)-1,1-dioxido-5-oxothiomorpholin-4-yl]acetate(71.7 mg, 0.145 mmol, 83%, from Step A) in MeOH (3 mL) was purged withnitrogen. The septum sealing the reaction vessel was briefly removed toallow introduction of Pd/C (˜14 mg, 10% Pd/C). The vessel was thenpurged with hydrogen from a balloon, before a fresh balloon of hydrogenwas attached. After 30 minutes the hydrogen atmosphere was replaced withnitrogen. The mixture was then filtered through a pad of celite, washingwith MeOH as needed. The filtrate was concentrated in vacuo to providethe title compound. MS: m/z=320 (M+1).

1-{[2-(Trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one Step A.1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine

Sodium hydride (60% dispersion in mineral oil; 16.2 g, 0.404 mol) wasadded in portions over 25 min to a solution of 7-azaindole (39.8 g,0.337 mol) in DMF (200 mL) at 0° C. and the mixture was stirred for 1 h.2-(Trimethylsilyl)ethoxymethyl chloride (71.8 mL, 0.404 mol) was thenadded slowly over 15 min, keeping the temperature of the reactionmixture below 10° C. After 1 h, the reaction was quenched with water(500 mL) and the mixture was extracted with CH₂Cl₂ (5×300 mL). Thecombined organic layers were washed with saturated brine, dried overMgSO₄, filtered, concentrated and dried under high vacuum to give thetitle compound. MS: m/z=249 (M+1).

Step B.3,3-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A solution of1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine from StepA (43.1 g, 0.1735 mol) in dioxane (300 mL) was added dropwise over 30min to a suspension of pyridine hydrobromide perbromide (277 g, 0.8677mol) in dioxane (300 mL). The reaction was stirred at ambienttemperature using an overhead mechanical stirrer to produce two layers.After 60 min, the reaction was quenched with water (300 mL) andextracted with EtOAc (500 mL). The aqueous layer was extracted furtherwith EtOAc (2×300 mL) and the combined organic layers were washed withH₂O (4×300 mL; the final wash was pH 5-6), then brine (300 mL), driedover MgSO₄, filtered and concentrated in vacuo. The crude product wasimmediately dissolved in CH₂Cl₂ and the solution filtered through a plugof silica, eluting with CH₂Cl₂ until the dark red color had completelyeluted from the plug. The filtrate was washed with saturated aqueousNaHCO₃ (400 mL), then brine (400 mL), dried over MgSO₄ filtered, andconcentrated in vacuo to give the title compound. MS: m/z=423 (M+1).

Step C.1-{[2-(Trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Zinc (100 g, 1.54 mol) was added to a solution of3,3-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(65 g, 0.154 mol) in THF (880 mL) and saturated aqueous NH₄Cl (220 mL).After 3 h, the reaction mixture was filtered and concentrated in vacuo.The residue was partitioned between EtOAc and H₂O which resulted in theformation of a white precipitate. Both layers were filtered through aCelite pad and the layers were separated. The aqueous layer was washedwith EtOAc (2×500 mL) and the combined organic layers were washed withH₂O, dried over MgSO₄, filtered, and concentrated under reducedpressure. The crude product was purified by silica gel chromatography,eluting with CH₂Cl₂:EtOAc—90:10, to give the title compound. MS: m/z=265(M+1).

1,2-Bis(bromomethyl)-4-nitrobenzene Step A.(4-Nitro-1,2-phenylene)dimethanol

A solution of 4-nitrophthalic acid (40 g, 189.5 mmol) in THF (500 mL)was added dropwise over 1.5 h to a solution of borane-THF complex (1 M,490 mL, 490 mmol), keeping the reaction temperature between 0° C. and 5°C. After the addition, the reaction mixture was allowed to warm slowlyto ambient temperature and stirred for 18 h. MeOH (100 mL) was addedcarefully and the precipitated solid dissolved. The mixture wasconcentrated in vacuo to about 500 mL, cooled to 0° C., and 10 N NaOHwas added to adjust the pH to 10-11. This mixture was extracted withEtOAc (3×600 mL) and the combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo to give the titlecompound. MS: m/z=207 (M−OH+CH₃CN).

Step B. 1,2-Bis(bromomethyl)-4-nitrobenzene

Phosphorus tribromide (20.1 mL, 212 mmol) in Et₂O (250 mL) was addeddropwise over 1.5 h to a solution of (4-nitro-1,2-phenylene)dimethanolfrom Step A (35.3 g, 193 mmol) in Et₂O (750 mL). After 18 h, thereaction mixture was cooled to 0° C. and quenched with H₂O (100 mL). Thelayers were separated and the organic layer was washed with H₂O (2×200mL), then saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound. MS: m/z=309 (M+1).

(R)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-oneStep A.(±)-5-Nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a solution of 1,2-bis(bromomethyl)-4-nitrobenzene (40.9 g, 132 mmol,described in Intermediate 8) and1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(31.5 g, 119 mmol, described in Intermediate 7) in DMF (2 L) was addedcesium carbonate (129 g, 397 mmol), portionwise, over 5 min. After 18 h,acetic acid (7.6 mL) was added and the mixture was concentrated to avolume of about 500 mL, then partitioned between EtOAc (1.5 L) and H₂O(1 L). The organic layer was washed with H₂O (1 L), then brine (500 mL),then dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS:m/z=412 (M+1).

Step B.(±)-5-Amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A mixture of 10% Pd/C (3 g) and(±)-5-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step A (19.1 g, 46.4 mmol) was stirred vigorously in EtOH (400 mL)under an atmosphere of hydrogen (ca. 1 atm). After 18 h, the mixture wasfiltered through a pad of Celite, washing extensively with MeOH, and thefiltrate was concentrated in vacuo to give the title compound. MS:m/z=382 (M+1).

Step C. tert-Butyl(R)-(2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)carbamate

A solution of(±)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step B (104 g, 273 mmol) and di-tert-butyl dicarbonate (71.5 g, 328mmol) in CHCl₃ (1 L) was heated to reflux for 17 h. The cooled mixturewas concentrated in vacuo and the residue was purified by silica gelchromatography, eluting with hexane:EtOAc—100:0 to 50:50, to give theracemic product. The enantiomers were resolved by HPLC, utilizing aChiralPak AD column and eluting with EtOH. The first major peak to elutewas tert-butyl(S)-(2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)carbamate,and the second major peak to elute was tert-butyl(R)-(2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)carbamate,the title compound. MS: m/z=482 (M+1).

Step D.(R)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A solution of tert-butyl(R)-(2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)carbamatefrom, Step C (13.4 g, 27.8 mmol) in MeOH (300 mL) was saturated with HCl(g). The mixture was resaturated with HCl (g) every 30 min until thestarting material was consumed, and then concentrated in vacuo. Theresidue was dissolved in MeOH (150 mL) and treated with ethylenediamine(1.9 mL, 27.8 mmol) and 10 N sodium hydroxide (6 mL, 60 mmol) to adjustthe mixture to pH 10. After 30 min, the mixture was diluted with H₂O(400 mL) and extracted with CHCl₃ (1 L). The organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude material wastriturated with MeOH (35 mL) to give the title compound. MS: m/z=252(M+1).

[(5R)-5-(3,5-Difluorophenyl)-2,2-dimethyl-3-oxomorpholin-4-yl]aceticacid Step A.N—[(S_(S),1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-(3,5-difluorophenyl)ethyl]-2-methylpropane-2-sulfinamide

To a stirred solution of(S_(S))—N-((1E)-2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene)-2-methylpropane-2-sulfinamide(5.00 g, 17.9 mmol) [Tang et al. (2001) J. Org. Chem., 66, 8772-8778] inTHF (75 mL) at −78° C. was added 3,5-difluorophenylmagnesium bromide(71.6 mL of a 0.5 M solution in THF, 35.8 mmol) dropwise. The reactionmixture was stirred at −78° C. for 5 h, and then allowed to warm slowlyto ambient temperature and stirring was continued for 18 h. The mixturewas quenched with saturated aqueous NH₄Cl (25 mL) and extracted withEtOAc (3×75 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of CH₂Cl₂:EtOAc—100:0to 80:20, to give the title compound. MS: m/z=392 (M+1).

Step B. (2R)-2-Amino-2-(3,5-difluorophenyl)ethanol

To a solution ofN—[(S_(S),1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,5-difluorophenyl)ethyl]-2-methylpropane-2-sulfinamidefrom Step A (1.50 g, 3.81 mmol) in MeOH (40 mL) at 0° C. was added HCl(9.5 mL of a 2 M solution in Et₂O, 19 mmol). After 20 min, the reactionmixture was concentrated to dryness in vacuo. The residue was dissolvedin H₂O (25 mL) and the mixture was extracted with EtOAc (2×50 mL) andthese organic extracts were discarded. The aqueous phase was adjusted topH 10 by addition of 1 N NaOH and extracted with EtOAc (2×50 mL). Theseorganic layers were dried over Na₂SO₄, filtered, and concentrated invacuo to give the title compound. MS: m/z=174 (M+1).

Step C. 2-Chloro-N-[(1R)-1-(3,5-difluorophenyl)-2-hydroxyethyl]acetamide

To a solution of (2R)-2-amino-2-(3,5-difluorophenyl)ethanol from Step B(630 mg, 3.64 mmol) and triethylamine (0.51 mL, 3.64 mmol) in CH₂Cl₂ (40mL) at 0° C. was added chloroacetyl chloride (0.29 mL, 3.64 mmol). After20 min, the reaction mixture was quenched with saturated aqueous NaHCO₃(15 mL) and extracted with CH₂Cl₂ (2×25 mL). The combined organicextracts were washed with 10% citric acid, then brine, then dried overNa₂SO₄, filtered, and concentrated in vacuo to give the title compound.MS: m/z=250 (M+1).

Step D. (5R)-5-(3,5-Difluorophenyl)morpholin-3-one

To a solution of2-chloro-N-[(1R)-1-(3,5-difluorophenyl)-2-hydroxyethyl]acetamide fromStep C (840 mg, 3.37 mmol) in THF (75 mL) at 0° C. was added NaH (291 mgof a 60% dispersion in oil, 7.28 mmol) and the mixture was stirred atambient temperature for 1 h. Saturated aqueous NH₄Cl (10 mL) was addedand the mixture was extracted with EtOAc (2×20 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc—75:25 to 25:75, to give the title compound. MS:m/z=214 (M+1).

Step E. tert-Butyl(3R)-3-(3,5-difluorophenyl)-5-oxomorpholine-4-carboxylate

A solution of (5R)-5-(3,5-difluorophenyl)morpholin-3-one from Step D(570 mg, 2.67 mmol), di-tert-butyl dicarbonate (584 mg, 2.67 mmol), and4-dimethylaminopyridine (327 mg, 2.67 mmol) in CH₂Cl₂ (30 mL) wasstirred at ambient temperature for 1 h. The solvent was removed underreduced pressure and the residue was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—90:10 to 50:50,to give the title compound. MS: m/z=377 (M+Na+CH₃CN).

Step F. tert-Butyl(5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxomorpholine-4-carboxylate

To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (1.60 mL,1.60 mmol) at −78° C. was added dropwise a solution of tert-butyl(3R)-3-(3,5-difluorophenyl)-5-oxomorpholine-4-carboxylate from Step E(500 mg, 1.60 mmol) in DME (15 mL) at −78° C. The resulting mixture wasstirred at −78° C. for 10 min then iodomethane (0.099 mL, 1.60 mmol) wasadded. After stirring at −78° C. for a further 1 h, the reaction mixturewas slowly transferred via cannula into a 1 M solution of sodiumbis(trimethylsilyl)amide in THF (1.60 mL, 1.60 mmol) at −78° C. Theresulting mixture was stirred at −78° C. for 10 min then a secondequivalent of iodomethane (0.099 mL, 1.60 mmol) was added. Afterstirring at −78° C. for a further 1 h, the reaction mixture was quenchedwith saturated aqueous NH₄Cl (10 mL) and extracted with EtOAc (2×25 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40,to give the title compound. MS: m/z=286 (M−C₄H₇).

Step G. (5R)-5-(3,5-Difluorophenyl)-2,2-dimethylmorpholin-3-one

To a solution of tert-butyl(5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxomorpholine-4-carboxylatefrom Step F (225 mg, 0.66 mmol) in CH₂Cl₂ (3 mL) at ambient temperaturewas added TFA (0.49 mL, 6.6 mmol). After stirring for 1 h, the reactionmixture was concentrated in vacuo to give the title compound. MS:m/z=242 (M+1).

Step H. Ethyl[(5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxomorpholin-4-yl]acetate

To a stirred solution of(5R)-5-(3,5-difluorophenyl)-2,2-dimethylmorpholin-3-one from Step G (150mg, 0.62 mmol) in DMF (2 mL) at 0° C. was added NaH (27 mg of a 60%dispersion in oil, 0.68 mmol). After 10 min, ethyl bromoacetate (104 mg,0.62 mmol) was added and the mixture was stirred at 0° C. for 30 min.Saturated aqueous NaHCO₃ (5 mL) was added and the mixture was extractedwith EtOAc (2×10 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—95:5 to 70:30, to give the title compound. MS: m/z=328(M+1).

Step I.[(5R)-5-(3,5-Difluorophenyl)-2,2-dimethyl-3-oxomorpholin-4-yl]aceticacid

To a solution of ethyl[(5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxomorpholin-4-yl]acetatefrom Step H (150 mg, 0.46 mmol) in THF (3 mL) and H₂O (3 mL) was added 1N aqueous LiOH (0.55 mL, 0.55 mmol) and the resulting mixture wasstirred at ambient temperature for 18 h. The reaction mixture waspurified directly by HPLC using a reversed phase C18 column and elutingwith a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1.Lyophilization provided the title compound. MS: m/z=300 (M+1).

Lithium [(2S,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate Step A.2-Chloro-N-[(1R)-2-hydroxy-1-phenylethyl]acetamide

To a solution of (R)-2-phenylglycinol (10 g, 73 mmol) and triethylamine(10.2 mL, 73 mmol) in CH₂Cl₂ (500 mL) at 0° C. was slowly addedchloroacetyl chloride (5.8 mL, 73 mmol). After 20 min, the reactionmixture was quenched with saturated aqueous NaHCO₃ (150 mL) andextracted with CH₂Cl₂ (2×250 mL). The combined organic extracts werewashed with 10% citric acid, then brine, then dried over Na₂SO₄,filtered, and concentrated in vacuo to give the title compound. MS:m/z=214 (M+1).

Step B. (5R)-5-Phenylmorpholin-3-one

To a solution of 2-chloro-N-[(1R)-2-hydroxy-1-phenylethyl]acetamide fromStep A (12.0 g, 56 mmol) in THF (750 mL) at 0° C. was added NaH (4.48 gof a 60% dispersion in oil, 112 mmol) in portions over 1 h and themixture was stirred at ambient temperature for 1 h. Saturated aqueousNH₄Cl (100 mL) was added and the mixture was extracted with EtOAc (2×200mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound. MS: m/z=178 (M+1).

Step C. tert-Butyl (5R)-3-oxo-5-phenylmorpholine-4-carboxylate

A solution of (5R)-5-phenylmorpholin-3-one from Step B (9.00 g, 50.8mmol), di-tert-butyl dicarbonate (11.1 g, 50.8 mmol), and4-dimethylaminopyridine (6.21 mg, 50.8 mmol) in CH₂Cl₂ (750 mL) wasstirred at ambient temperature for 18 h. The solvent was removed underreduced pressure and the residue was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—50:50 to 0:100,to give the title compound. MS: m/z=222 (M−C₄H₇).

Step D. tert-Butyl(2S,5R)-2-methyl-3-oxo-5-phenylmorpholine-4-carboxylate

To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (0.79 mL,0.79 mmol) at −78° C. was added dropwise a solution of tert-butyl(5R)-3-oxo-5-phenylmorpholine-4-carboxylate from Step C (200 mg, 0.72mmol) in DME (5 mL) at −78° C. The resulting mixture was stirred at −78°C. for 10 min then iodomethane (0.049 mL, 0.79 mmol) was added. Afterstirring at −78° C. for a further 1 h, the reaction mixture was quenchedwith saturated aqueous NH₄Cl (5 mL) and extracted with EtOAc (2×10 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was partially purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10to 60:40. Further purification was achieved by HPLC, using a ChiralPakAS column and eluting with hexane:i-PrOH—90:10, to give the titlecompound. MS: m/z=236 (M−C₄H₇).

Step E. (2S,5R)-2-Methyl-5-phenylmorpholin-3-one

To a solution of tert-butyl(2S,5R)-2-methyl-3-oxo-5-phenylmorpholine-4-carboxylate from Step D (160mg, 0.55 mmol) in CH₂Cl₂ (2 mL) at ambient temperature was added TFA(0.41 mL, 5.5 mmol). After stirring for 1 h, the reaction mixture wasconcentrated in vacuo to give the title compound. MS: m/z=192 (M+1).

Step F. Ethyl [(2S,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate

To a stirred solution of (2S,5R)-2-methyl-5-phenylmorpholin-3-one fromStep E (90 mg, 0.47 mmol) in DMF (2 mL) at 0° C. was added NaH (20 mg ofa 60% dispersion in oil, 0.50 mmol). After 10 min, ethyl bromoacetate(79 mg, 0.47 mmol) was added and the mixture was stirred at 0° C. for 2h. Saturated aqueous NaHCO₃ (3 mL) was added and the mixture wasextracted with EtOAc (2×30 mL). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—90:10 to 60:40, to give the title compound. MS: m/z=278(M+1).

Step G. Lithium [(2S,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate

To a solution of ethyl[(2S,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate from Step F (125mg, 0.45 mmol) in THF (4 mL) and H₂O (4 mL) was added 1 N aqueous LiOH(0.54 mL, 0.54 mmol) and the resulting mixture was stirred at ambienttemperature for 18 h. The mixture was adjusted to pH 6 by addition of 1N HCl and concentrated to dryness in vacuo to give the title compound.MS: m/z=250 (M+1).

Lithium [(2R,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate Step A.2-Chloro-N-[(1R)-2-hydroxy-1-phenylethyl]propanamide

To a solution of (R)-2-phenylglycinol (1.00 g, 7.3 mmol) andtriethylamine (1.02 mL, 7.3 mmol) in CH₂Cl₂ (50 mL) at 0° C. was slowlyadded 2-chloropropionyl chloride (0.72 mL, 7.3 mmol). After 20 min, thereaction mixture was quenched with saturated aqueous NaHCO₃ (20 mL) andextracted with CH₂Cl₂ (2×50 mL). The combined organic extracts werewashed with 10% citric acid, then brine, then dried over Na₂SO₄,filtered, and concentrated in vacuo to give the title compound. MS:m/z=228 (M+1).

Step B. (2R,5R)-2-Methyl-5-phenylmorpholin-3-one

To a solution of 2-chloro-N-[(1R)-2-hydroxy-1-phenylethyl]propanamidefrom Step A (1.30 g, 5.71 mmol) in THF (100 mL) at 0° C. was added NaH(493 mg of a 60% dispersion in oil, 12.3 mmol) and the mixture wasstirred at ambient temperature for 18 h. Saturated aqueous NaHCO₃ (10mL) was added and the mixture was extracted with EtOAc (3×20 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—75:25 to 0:100,to give the title compound. MS: m/z=192 (M+1).

Step C. Ethyl [(2R,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate

To a stirred solution of (2R,5R)-2-methyl-5-phenylmorpholin-3-one fromStep B (500 mg, 2.62 mmol) in DMF (15 mL) at 0° C. was added NaH (113 mgof a 60% dispersion in oil, 2.83 mmol). After 10 min, ethyl bromoacetate(437 mg, 2.62 mmol) was added and the mixture was stirred at 0° C. for 2h. Saturated aqueous NaHCO₃ (3 mL) was added and the mixture wasextracted with EtOAc (2×30 mL). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—90:10 to 60:40, to give the title compound. MS: m/z=278(M+1).

Step D. Lithium [(2S,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate

To a solution of ethyl[(2R,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate from Step C (590mg, 2.13 mmol) in THF (5 mL) and H₂O (5 mL) was added 1 N aqueous LiOH(2.55 mL, 2.55 mmol) and the resulting mixture was stirred at ambienttemperature for 18 h. The mixture was adjusted to pH 6 by addition of 1N HCl and concentrated to dryness in vacuo to give the title compound.MS: m/z=250 (M+1).

Lithium[(6R)-4-(tert-butoxycarbonyl)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperazin-1-yl]acetateStep A. Methyl2-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}-2-methylpropanoate

A mixture of methyl α-aminoisobutyrate hydrochloride (10.3 g, 67.0mmol), 3,5-difluorophenacyl bromide (15.0 g, 63.8 mmol), and K₂CO₃ (17.6g, 128 mmol) in DMF (100 mL) was stirred at ambient temperature for 3 h.Saturated aqueous NaHCO₃ (400 mL) was added and the mixture wasextracted with EtOAc (1 L). The organic layer was washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS:m/z=272 (M+1).

Step B. (±)-Ethyl[6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperazin-1-yl]acetate

A mixture of methyl2-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}-2-methylpropanoate fromStep A (8.60 g, 31.7 mmol), glycine ethyl ester hydrochloride (44.3 g,317 mmol), and AcOH (5.71 mL, 95 mmol) in MeOH (300 mL) was stirred atambient temperature for 10 min. NaCNBH₃ (2.39 g, 38.0 mmol) was addedand the pH of the mixture was checked and adjusted to pH ˜5 asnecessary. The reaction mixture was heated to 50° C. for 18 h.Additional AcOH (4 mL) was added and the reaction mixture was heated to60° C. for 6 h then allowed to cool and concentrated in vacuo to avolume of ca. 150 mL. The resulting mixture was carefully quenched withsaturated aqueous NaHCO₃ (300 mL) and then extracted with CH₂Cl₂ (1 L).The organic extract was washed with brine, dried over Na₂SO₄, filtered,and concentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with hexane:EtOAc—100:0 to 0:100, to give thetitle compound. MS: m/z=327 (M+1).

Step C. tert-Butyl(5R)-5-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-3-oxopiperazine-1-carboxylate

A solution of ethyl[8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate fromStep B (2.27 g, 6.96 mmol), N,N-diisopropylethylamine (0.607 mL, 3.48mmol), and di-tert-butyl dicarbonate (15.2 g, 69.6 mmol) in acetonitrile(30 mL) was stirred at 60° C. for 18 h, then cooled and concentratedunder reduced pressure. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100,to give the racemic product. The enantiomers were separated by SFC,using a Chiralcel OD column and eluting with CO₂:MeOH—80:20. The firstmajor peak to elute was tert-butyl(5S)-5-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-3-oxopiperazine-1-carboxylateand the second major peak to elute was tert-butyl(5R)-5-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-3-oxopiperazine-1-carboxylate,the title compound. MS: m/z=371 (M−C₄H₇).

Step D. Lithium[(6R)-4-(tert-butoxycarbonyl)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperazin-1-yl]acetate

To a solution of tert-butyl(5R)-5-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-3-oxopiperazine-1-carboxylatefrom Step C (1.18 g, 2.77 mmol) in THF (18 mL) and H₂O (2 mL) was added1 N aqueous LiOH (3.04 mL, 3.04 mmol) and the resulting mixture wasstirred at ambient temperature for 5 h. The mixture was adjusted to pH 6by addition of 1 N HCl and concentrated to dryness in vacuo to give thetitle compound. MS: m/z=343 (M−C₄H₇).

(S)-[6-(3-Fluoro-4-methylphenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]aceticacid Step A. (S)-6-(3-Fluoro-4-methylphenyl)-3,3-dimethylpiperidin-2-one

To a stirred solution of benzyl(S_(S))-5-[(tert-butylsulfinyl)imino]-2,2-dimethylpentanoate (1.00 g,2.96 mmol, described in Intermediate 3) in toluene (28 mL) at −78° C.was added 3-fluoro-4-methylphenylmagnesium bromide (11.9 mL of a 0.5 Msolution in THF, 5.93 mmol). The reaction mixture was warmed to ambienttemperature for 2 h, and then heated at reflux for 2 h. The solvent wasremoved in vacuo and the crude solid dissolved in DMSO (5 mL). The crudeproduct was purified by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1.Lyophilization provided the title compound. MS: m/z=236 (M+1).

Step B.(S)-[6-(3-Fluoro-4-methylphenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]aceticacid

To a stirred solution of(S)-6-(3-fluoro-4-methylphenyl)-3,3-dimethylpiperidin-2-one from Step A(80 mg, 0.340 mmol) in DMF (3 mL) at ambient temperature was added NaH(19 mg of a 60% dispersion in oil, 0.476 mmol). After 15 min, methylbromoacetate (0.051 mL, 0.544 mmol) was added and the mixture wasstirred for 16 h. Sodium hydroxide (0.061 mL of a 10 M solution, 0.612mmol) was added and the mixture stirred for 2 h. The crude product waspurified directly by HPLC using a reversed phase C18 column and elutingwith a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The compoundwas further purified by SFC, utilizing a ChiralPak AD column and elutingwith CO₂:MeOH—91:9, to give the title compound. MS: m/z=294 (M+1).

{(±)-3,3-Dimethyl-2-oxo-6-[3-(trifluoromethyl)phenyl]piperidin-1-yl}aceticacid Step A. Methyl2,2-dimethyl-5-oxo-5-[3-(trifluoromethyl)phenyl]pentanoate

To a stirred solution of 3-bromobenzenetrifluoride (337 mg, 1.50 mmol)in THF (3 mL) at −78° C. was added tert-butyllithium (1.76 mL of a 1.7 Msolution in pentane, 2.99 mmol) dropwise. The reaction mixture wasstirred for 1 h at −78° C., and then a solution of methyl5-[methoxy(methyl)amino]-2,2-dimethyl-5-oxopentanoate (325 mg, 1.50mmol, described in Intermediate 1) in THF (5 mL) was added. The reactionmixture was stirred for 1 h at −78° C. The solvent was removed in vacuoand the crude solid dissolved in DMSO (5 mL). The crude product waspurified by HPLC using a reversed phase C18 column and eluting with agradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Lyophilizationprovided the title compound. MS: m/z=303 (M+1).

Step B.{(±)-3,3-Dimethyl-2-oxo-6-[3-(trifluoromethyl)phenyl]piperidin-1-yl}aceticacid

To a stirred solution of methyl2,2-dimethyl-5-oxo-5-[3-(trifluoromethyl)phenyl]pentanoate from Step A(45.0 mg, 0.149 mmol) and glycine (99.0 mg, 1.32 mmol) in MeOH (2 mL)and acetic acid (0.045 mL) was added sodium cyanoborohydride (50.0 mg,0.794 mmol). The reaction mixture was heated to reflux for 18 h. To theresulting mixture was added xylenes (3 mL) and heated to 140° C. for 4h. The solvent was removed in vacuo and the crude solid dissolved inDMSO (1 mL). The crude product was purified by HPLC using a reversedphase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Lyophilization provided thetitle compound. MS: m/z=330 (M+1).

3,3-Dimethyl-2-oxo-6-[4-(trifluoromethyl)phenyl]piperidin-1-yl}aceticacid Step A. 3,3-Dimethyl-6-[4-(trifluoromethyl)phenyl]piperidin-2-one

To a stirred solution of 4-bromobenzenetrifluoride (333 mg, 1.48 mmol)in THF (3 mL) at −78° C. was added tert-butyllithium (1.74 mL of a 1.7 Msolution in pentane, 2.96 mmol) dropwise. The reaction mixture wasstirred for 1 h at −78° C., and then a solution of benzyl(S_(S))-5-[(tert-butylsulfinyl)imino]-2,2-dimethylpentanoate (250 mg,0.741 mmol, described in Intermediate 3) in toluene (5 mL) was added.The reaction mixture was stirred for 20 min at −78° C., 1 h at ambienttemperature, and 1 h at reflux. The solvent was removed in vacuo and thecrude solid dissolved in DMSO (5 mL). The crude product was purified byHPLC using a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Lyophilization provided thetitle compound. MS: m/z=272 (M+1).

3,3-Dimethyl-2-oxo-6-[4-(trifluoromethyl)phenyl]piperidin-1-yl}aceticacid

Essentially following the procedures described for Intermediate 14, butusing 3,3-dimethyl-6-[4-(trifluoromethyl)phenyl]piperidin-2-one in placeof (S)-6-(3-fluoro-4-methylphenyl)-3,3-dimethylpiperidin-2-one, thetitle compound was prepared. MS: m/z=330 (M+1).

[6-(6-Bromo-2,3,4-trifluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]aceticacid Step A.6-(6-Bromo-2,3,4-trifluorophenyl)-3,3-dimethylpiperidin-2-one

To a stirred solution of 1-bromo-3,4,5-trifluorobenzene (313 mg, 1.48mmol) in THF (3 mL) at −78° C. was added tert-butyllithium (1.74 mL of a1.7 M solution in pentane, 2.96 mmol) dropwise. The reaction mixture wasstirred for 1 h at −78° C., 3 h at 0° C., and then cooled back down to−78° C. A solution of benzyl(S_(S))-5-[(tert-butylsulfinyl)imino]-2,2-dimethylpentanoate (250 mg,0.741 mmol, described in Intermediate 3) in toluene (5 mL) was added.The reaction mixture was stirred for 20 min at −78° C., 16 h at ambienttemperature, and 1 h at reflux. The solvent was removed in vacuo and thecrude solid dissolved in DMSO (5 mL). The crude product was purified byHPLC using a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Lyophilization provided thetitle compound. MS: m/z=337 (M+1).

[6-(6-Bromo-2,3,4-trifluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]aceticacid

Essentially following the procedures described for Intermediate 14, butusing 6-(6-bromo-2,3,4-trifluorophenyl)-3,3-dimethylpiperidin-2-one inplace of (S)-6-(3-fluoro-4-methylphenyl)-3,3-dimethylpiperidin-2-one,the title compound was prepared. MS: m/z=395 (M+1).

[3,3-Dimethyl-2-oxo-6-(2,3,4-trifluorophenyl)piperidin-1-yl]acetic acidStep A. 3,3-Dimethyl-6-(2,3,4-trifluorophenyl)piperidin-2-one

A solution of6-(6-bromo-2,3,4-trifluorophenyl)-3,3-dimethylpiperidin-2-one (27.0 mg,0.080 mmol, described in Intermediate 17) and 10% palladium on carbon indegassed EtOH (2 mL) was stirred under a hydrogen balloon for 3 h. Thereaction mixture was filtered through a Celite pad and concentrated invacuo to provide the title compound. MS: m/z=258 (M+1).

[3,3-Dimethyl-2-oxo-6-(2,3,4-trifluorophenyl)piperidin-1-yl]acetic acid

Essentially following the procedures described for Intermediate 14, butusing 3,3-dimethyl-6-(2,3,4-trifluorophenyl)piperidin-2-one in place of(S)-6-(3-fluoro-4-methylphenyl)-3,3-dimethylpiperidin-2-one, the titlecompound was prepared. MS: m/z=316 (M+1).

Lithium [(3R)-3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yl]acetate Step A.Methyl (2R)-2-[(2-oxo-2-phenylethyl)amino]propanoate, TFA salt

A mixture of (R)-alanine methyl ester hydrochloride (1.00 g, 7.16 mmol),2-bromoacetophenone (2.85 g, 14.3 mmol), and NaHCO₃ (1.20 g, 14.3 mmol)in DMF (20 mL) was stirred at ambient temperature for 6 h. The reactionmixture was quenched with 1 N aqueous HCl (25 mL) and the mixture wasextracted with EtOAc (2×35 mL) and the organic phase was discarded. Theaqueous phase was adjusted to pH 10 with saturated aqueous Na₂CO₃ andthen extracted with EtOAc (3×75 mL). The combined organic extracts weredried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1.Concentration of product-containing fractions in vacuo provided thetitle compound. MS: m/z=222 (M+1).

Step B. Methyl [(3R)-3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yl]acetate

To a stirred mixture of methyl(2R)-2-[(2-oxo-2-phenylethyl)amino]propanoate, TFA salt, from Step A(152 mg, 0.452 mmol) and glycine methyl ester hydrochloride (85 mg,0.678 mmol) in MeOH (1 mL) was added N,N-diisopropylethylamine (0.197mL, 1.13 mmol), followed by AcOH (0.155 mL, 2.71 mmol). The resultingmixture was stirred at ambient temperature for 10 min, then NaCNBH₃ (34mg, 0.54 mmol) was added. The reaction mixture was heated to 50° C. for18 h then allowed to cool. Formaldehyde (0.067 mL of a 37% aqueoussolution, 0.90 mmol) was added and the mixture was stirred at ambienttemperature for 30 min. The reaction mixture was quenched with 1 Naqueous HCl (5 mL) and the mixture was extracted with EtOAc (2×10 mL)and the organic phase was discarded. The aqueous phase was adjusted topH 10 with saturated aqueous Na₂CO₃ and then extracted with EtOAc (3×15mL). The combined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by HPLC using areversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The product-containingfractions were combined, basified with saturated aqueous NaHCO3, andextracted with EtOAc. The organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo to provide the title compound. MS:m/z=277 (M+1).

Step C. Lithium [(3R)-3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yl]acetate

A solution of methyl[(3R)-3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yl]acetate from Step B (50mg, 0.18 mmol) in THF (1 mL) was added 1 N aqueous LiOH (0.20 mL, 0.20mmol) and the resulting mixture was stirred at ambient temperature for 4h. The mixture was adjusted to pH 6 by addition of 1 N HCl andconcentrated to dryness in vacuo to give the title compound. MS: m/z=263(M+1).

[(5R)-2,2-Diethyl-3-oxo-5-phenylmorpholin-4-yl]acetic acid Step A.2-Chloro-N-[(1R)-2-hydroxy-1-phenylethyl]butanamide

To a solution of (R)-2-phenylglycinol (2.00 g, 14.6 mmol) andtriethylamine (2.03 mL, 14.6 mmol) in CH₂Cl₂ (100 mL) at 0° C. wasslowly added 2-chlorobutyryl chloride (1.66 mL, 14.6 mmol). After 30min, the reaction mixture was quenched with saturated aqueous NaHCO₃ (30mL) and extracted with CH₂Cl₂ (2×75 mL). The combined organic extractswere washed with 10% citric acid, then brine, then dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—70:30to 0:100, to give the title compound. MS: m/z=242 (M+1).

Step B. (2R,5R)-2-Ethyl-5-phenylmorpholin-3-one

To a solution of 2-chloro-N-[(1R)-2-hydroxy-1-phenylethyl]butanamidefrom Step A (2.75 g, 11.4 mmol) in THF (200 mL) at 0° C. was added NaH(983 mg of a 60% dispersion in oil, 24.6 mmol) and the mixture wasstirred at ambient temperature for 18 h. Saturated aqueous NaHCO₃ (20mL) was added and the mixture was extracted with EtOAc (3×40 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—75:25 to 0:100,to give the title compound. MS: m/z=206 (M+1).

Step C. tert-Butyl(2R,5R)-2-ethyl-3-oxo-5-phenylmorpholine-4-carboxylate

A solution of (2R,5R)-2-ethyl-5-phenylmorpholin-3-one from Step B (900mg, 4.41 mmol), di-tert-butyl dicarbonate (962 mg, 4.41 mmol), and4-dimethylaminopyridine (538 mg, 4.41 mmol) in CH₂Cl₂ (50 mL) wasstirred at ambient temperature for 4 h. The mixture was washed with 10%citric acid (35 mL), then dried over Na₂SO₄, filtered, and concentratedin vacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc—95:5 to 60:40, to give the titlecompound. MS: m/z=250 (M−C₄H₇).

Step D. tert-Butyl(5R)-2,2-diethyl-3-oxo-5-phenylmorpholine-4-carboxylate

To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (1.64 mL,1.64 mmol) at −78° C. was added dropwise a solution of tert-butyl(2R,5R)-2-ethyl-3-oxo-5-phenylmorpholine-4-carboxylate from Step C (500mg, 1.64 mmol) in DME (25 mL) at −78° C. The resulting mixture wasstirred at −78° C. for 10 min then iodoethane (0.131 mL, 1.64 mmol) wasadded. After stirring at −78° C. for 30 min, then at −30° C. for 30 min,the reaction mixture was cooled to −78° C. and quenched with saturatedaqueous NH₄Cl (20 mL) then extracted with EtOAc (2×40 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc—95:5 to 70:30, to give the titlecompound. MS: m/z=278 (M−C₄H₇).

Step E. [(5R)-2,2-Diethyl-3-oxo-5-phenylmorpholin-4-yl]acetic acid

Essentially following the procedures described for Intermediate 10, butusing tert-butyl (5R)-2,2-diethyl-3-oxo-5-phenylmorpholine-4-carboxylatein place of tert-butyl(5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxomorpholine-4-carboxylate,the title compound was prepared. MS: m/z=292 (M+1).

[(4S,6S)-6-(3,5-Difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]aceticacid Step A. 6-(3,5-Difluorophenyl)-3,3-dimethylpiperidine-2,4-dione

To a solution of 3,3-dimethylpyridine-2,4(1H,3H)-dione (978 mg, 7.03mmol) [U.S. Pat. No. 2,525,231] in benzene (10 mL) was added3,5-difluorophenylmagnesium bromide (50 mL of a 0.5 M solution in THF,25 mmol) and the resulting mixture was heated to reflux for 1.5 h. Themixture was cooled, quenched with 1 N aqueous HCl (10 mL), made basicwith saturated NaHCO₃ solution (100 mL) and extracted with EtOAc (2×150mL). The combined organic layers were washed with H₂O (50 mL), thenbrine (50 mL), and dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc—100:0 to 60:40, to give thetitle compound. MS: m/z=254 (M+1).

Step B. cis-6-(3,5-Difluorophenyl)-4-hydroxy-3,3-dimethylpiperidin-2-one

To a solution of 6-(3,5-difluorophenyl)-3,3-dimethylpiperidine-2,4-dionefrom Step A (20.18 g, 80 mmol) in THF (600 mL) and CH₃OH (25 mL) at 0°C. was added NaBH₄ (4.57 g, 121 mmol). After 2.5 h, the reaction mixturewas quenched with H₂O (200 mL) and concentrated in vacuo. The residuewas partitioned between H₂O (600 mL), saturated aqueous NaHCO₃ (200 mL)and EtOAc (1 L). The organic layer was separated and the aqueous layerwas extracted with EtOAc (600 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:CH₃OH—100:0 to 88:12, to give the title compound,which contained approximately 20% of the corresponding trans-isomer. MS:m/z=256 (M+1).

Step C. Ethyl[(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate

To a solution ofcis-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethylpiperidin-2-one fromStep B (17.1 g, 67.0 mmol) in THF (400 mL) at 0° C. was added NaH (60%dispersion in oil, 4.91 g, 73.7 mmol). After 30 min, ethyl bromoacetate(8.20 mL, 73.7 mmol) was added. After 30 min, the reaction mixture wasquenched with saturated aqueous NH₄Cl (100 mL), diluted with H₂O (700mL) and brine (100 mL) and extracted with EtOAc (700 mL). The organicextract was dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc—100:0 to 0:100, to give the alcohol as amixture of four isomers. Additional purification was achieved by HPLC,using a ChiralPak AD column and eluting withhexane:EtOH:Et₂NH—90:10:0.1. The first major peak to elute was a mixtureof ethyl[(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetateand ethyl[(4S,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate(ca. 5:1). The second major peak to elute was a mixture of ethyl[(4R,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetateand ethyl[(4R,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate(ca. 3:1). Further purification of the second major peak was achieved bySFC, using a ChiralPak AD column and eluting withCO₂:MeOH:Et₂NH—90:10:0.1, to give ethyl[(4R,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate,which eluted first, and ethyl[(4R,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate,which eluted second. Further purification of the first major peak wasachieved by SFC, using a ChiralPak AD column and eluting withCO₂:MeOH:Et₂NH—90:10:0.1, to give ethyl[(4S,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate,which eluted first, and ethyl[(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate,which eluted second, the title compound. MS: m/z=342 (M+1).

Step D.[(4S,6S)-6-(3,5-Difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]aceticacid

To a solution of ethyl[(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetatefrom Step C (64 mg, 187 mmol) in THF (1 mL) and H₂O (0.5 mL) was addedLiOH monohydrate (14 mg, 334 mmol) and the resulting mixture was stirredat ambient temperature for 1 h. The reaction mixture was quenched with 1N HCl (0.40 mL, 400 mmol), concentrated in vacuo and dried to afford thetitle compound. MS: m/z=314 (M+1).

[(6S)-6-(3,5-Difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]aceticacid Step A. Ethyl[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]acetate

To a solution of ethyl[(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate(470 mg, 1.377 mmol, described in Intermediate 21) in acetone (24 mL) at0° C. was added a solution of chromium (VI) trioxide (174 mg, 1.740mmol) in H₂O (0.5 mL) and H₂SO₄ (0.147 mL, 2.75 mmol), in three portionsover 5 min and the mixture was stirred at 0° C. for 30 min. Most of theacetone was removed by concentration in vacuo, and the residue wasbasified with saturated aqueous NaHCO₃ (75 mL) and extracted with EtOAc(2×100 mL). The combined organic layers were washed with brine (40 mL)and dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:CH₃OH—100:0 to 92:8, to give the title compound. MS:m/z=340 (M+1).

Step B.[(6S)-6-(3,5-Difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]aceticacid

To a solution of ethyl[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]acetatefrom Step A (170 mg, 0.501 mmol) in THF (2 mL) and H₂O (1 mL) was addedLiOH monohydrate (36 mg, 0.858 mmol) and the resulting mixture wasstirred at ambient temperature for 18 h. The reaction mixture wasquenched with 1 N HCl (1 mL, 1 mmol), concentrated in vacuo and dried toafford the title compound. MS: m/z=312 (M+1).

[2-(3,4-Difluorophenyl)-5,5-dimethylpiperidin-1-yl]acetic acid Step A.2-(3,4-Difluorophenyl)-5,5-dimethylpiperidine

To a stirred solution of6-(3,4-difluorophenyl)-3,3-dimethylpiperidin-2-one (50.0 mg, 0.209 mmol,prepared according to Intermediate 14, Step A) in THF (1 mL) at 0° C.was added diisobutylaluminum hydride (1.05 mL of a 1 M solution intoluene, 1.05 mmol). The reaction mixture was stirred for 4 days, withadditional diisobutylaluminum hydride (1.05 mL of a 1 M solution intoluene, 1.05 mmol) added on the 2^(nd) and 3^(rd) days. The reactionwas quenched with saturated potassium sodium tartrate (5 mL) andextracted with EtOAc (3×10 mL). The combined organic extracts were driedover MgSO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofMeOH:CH₂Cl₂—0:100 to 5:95, to give the title compound. MS: m/z=226(M+1).

Step B. [6-(3,4-Difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]aceticacid

To a stirred solution of 2-(3,4-difluorophenyl)-5,5-dimethylpiperidinefrom Step A (47.0 mg, 0.209 mmol) in THF (2 mL) at 0° C. was added NaH(12.0 mg of a 60% dispersion in oil, 0.292 mmol). After 15 min, methylbromoacetate (0.022 mL, 0.229 mmol) was added and the mixture wasstirred at ambient temperature for 4 d, with additional methylbromoacetate (0.022 mL, 0.229 mmol) added on the 2^(nd) and 3^(rd) days.Added NaOH (0.627 mL of a 1M solution) and the mixture was stirred at50° C. for 16 h. The reaction mixture was acidified with 1 M HCl (5 mL)and extracted with EtOAc (3×10 mL). The combined organic extracts werewashed with brine (5 mL), dried over Na₂SO₄, filtered, and concentratedin vacuo to provide the title compound. MS: m/z=284 (M+1).

[(5R)-2,2-Diethyl-5-(3,5-difluorophenyl)-3-oxomorpholin-4-yl]acetic acidStep A.2-Chloro-N-[(1R)-1-(3,5-difluorophenyl)-2-hydroxyethyl]butanamide

To a solution of (2R)-2-amino-2-(3,5-difluorophenyl)ethanol (2.60 g,15.0 mmol, described in Intermediate 10) and triethylamine (4.19 mL,30.0 mmol) in CH₂Cl₂ (150 mL) at 0° C. was slowly added 2-chlorobutyrylchloride (1.71 mL, 15.0 mmol). After 60 min, the reaction mixture wasquenched with saturated aqueous NaHCO₃ (40 mL) and extracted with CH₂Cl₂(2×100 mL). The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—70:30to 0:100, to give the title compound. MS: m/z=278 (M+1).

[(5R)-2,2-Diethyl-5-(3,5-difluorophenyl)-3-oxomorpholin-4-yl]acetic acid

Essentially following the procedures described for Intermediate 20, butusing 2-chloro-N-[(1R)-1-(3,5-difluorophenyl)-2-hydroxyethyl]butanamidein place of 2-chloro-N-[(1R)-2-hydroxy-1-phenylethyl]butanamide, thetitle compound was prepared. MS: m/z=328 (M+1).

Lithium[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetateStep A. Methyl 1-aminocyclopentanecarboxylate hydrochloride

A solution of 1-aminocyclopentanecarboxylic acid (2.00 g, 15.5 mmol) inMeOH (30 mL) was saturated with HCl (g). The resulting mixture was agedat ambient temperature for 2 h and concentrated in vacuo to provide thetitle compound. MS: m/z=144 (M+1).

Step B. Methyl1-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}cyclopentanecarboxylate

A mixture of methyl 1-aminocyclopentanecarboxylate hydrochloride fromStep A (1.50 g, 10.5 mmol), 3,5-difluorophenacyl bromide (3.20 g, 13.6mmol), and NaHCO₃ (1.32 g, 15.7 mmol) in DMF (30 mL) was stirred atambient temperature for 6 h. 1 N aqueous HCl (50 mL) was added and themixture was extracted with EtOAc (75 mL) and this organic extract wasdiscarded. The aqueous layer was adjusted to pH 10 by addition ofsaturated aqueous Na₂CO₃ (150 mL) and the mixture was extracted withEtOAc (3×75 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Theproduct-containing fractions were combined and concentrated to providethe title compound as the TFA salt. MS: m/z=298 (M+1).

Step C. Ethyl[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate

To a stirred mixture of methyl1-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}cyclopentanecarboxylate, TFAsalt, from Step B (1.10 g, 2.67 mmol) and glycine ethyl esterhydrochloride (560 mg, 4.01 mmol) in MeOH (7.5 mL) was addedN,N-diisopropylethylamine (1.17 mL, 6.69 mmol), followed by AcOH (0.77mL, 13.4 mmol). The resulting mixture was stirred at ambient temperaturefor 10 min, then NaCNBH₃ (252 mg, 4.01 mmol) was added. The reactionmixture was heated to 60° C. for 72 h then allowed to cool. The reactionmixture was quenched with saturated aqueous NaHCO₃ and then extractedwith EtOAc (3×50 mL). The combined organic extracts were dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by HPLC using a reversed phase C18 column and eluting with agradient of 1-120:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Theproduct-containing fractions were combined, basified with saturatedaqueous NaHCO₃, and extracted with EtOAc. The organic extracts weredried over Na₂SO₄, filtered, and concentrated in vacuo to give theracemic product. The enantiomers were separated by SFC, using aChiralPak AD column and eluting with CO₂:MeOH—90:10. The first majorpeak to elute was ethyl[(8S)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate,and the second major peak to elute was ethyl[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate,the title compound. MS: m/z=353 (M+1).

Step D. Lithium[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate

To a solution of ethyl[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetatefrom Step C (90 mg, 0.26 mmol) in THF (3 mL) and H₂O (1 mL) was added 1N aqueous LiOH (0.31 mL, 0.31 mmol) and the resulting mixture wasstirred at ambient temperature for 1 h. The mixture was adjusted to pH 6by addition of 1 N HCl and concentrated to dryness in vacuo to give thetitle compound. MS: m/z=325 (M+1).

[(6S)-6-(3,5-Difluorophenyl)-3,3-diethyl-2-oxopiperidin-1-yl]acetic acidStep A. Ethyl(5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)pentanoate

To a solution of ethyl 5-(3,5-difluorophenyl)-5-oxovalerate (5.00 g,19.5 mmol) and (S)-2-methylpropane-2-sulfinamide (2.88 g, 23.8 mmol) inTHF (123 mL) was added titanium tetraethoxide (8.18 mL, 39.0 mmol). Thereaction vessel was quickly sealed and placed into a 60° C. bath for 16h. After cooling to ambient temperature a septum and nitrogen inlet wereattached prior to cooling to 0° C. Sodium borohydride (1.48 g, 39.0mmol) was then added, and a complete reaction was observed after 1 h.Methyl alcohol was then slowly added until gas evolution had stopped.The reaction mixture was then diluted with brine (60 mL) whileexperiencing rapid stirring. The resultant slurry was filtered throughcelite, washing with EtOAc as needed. The combined organics were thenwashed with brine, dried over sodium sulfate, filtered and concentratedin vacuo to give an oil. This oil was purified by silica gelchromatography, eluting with a gradient of EtOAc:Hexanes—10:90 to 50:50,to give the title compound. MS: m/z=362 (M+1).

Step B. (6S)-6-(3,5-Difluorophenyl)-piperidin-2-one

A solution of ethyl(5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)pentanoatefrom Step A (4.42 g, 12.2 mmol) in MeOH (200 mL) was cooled to 0° C.Hydrogen chloride gas (anhydrous) was bubbled through this cold solutionfor about 1 minute, after which time the reaction vessel was sealed andallowed to sit in the ice bath for 15 minutes. Dry nitrogen was thenbubbled through the solution for 30 minutes, prior to removal of solventin vacuo. More MeOH (˜50 mL) was added, and then removed in vacuo. Afterdissolving in a third volume of MeOH (100 mL), triethylamine (6.78 mL,48.9 mmol) was introduced and the mixture was heated to 65° C. for 3hours. After cooling to ambient temperature, the solvent was removed invacuo and the residue was partitioned between diethyl ether (100 mL) and1 M HCl (50 mL). The organics were washed with additional 1 M HCl (50mL), water (50 mL) and saturated brine (50 mL). The ethereal solutionwas dried over sodium sulfate, filtered and then concentrated in vacuoto provide the title compound, which could be used without furtherpurification. MS: m/z=212 (M+1).

Step C. tert-Butyl(2S)-2-(3,5-difluorophenyl)-6-oxopiperidine-1-carboxylate

A solution of (6S)-6-(3,5-difluorophenyl)-piperidin-2-one from Step B(2.08 g, 9.85 mmol), di-tert-butyl dicarbonate (4.30 g, 19.7 mmol), and4-dimethylaminopyridine (1.20 g, 9.85 mmol) in CH₂Cl₂ (50 mL) wasstirred at ambient temperature for 20 h. An additional portion ofdi-tert-butyl dicarbonate (1.25 g, 5.73 mmol) was added and the solutionstirred for a further 16 h. The solvent was removed under reducedpressure and the residue was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give thetitle compound. MS: m/z=256 (M−C₄H₇).

Step D. tert-Butyl(6S)-6-(3,5-difluorophenyl)-3,3-diethylpiperidin-2-one-1-carboxylate

To a solution of tert-butyl(2S)-2-(3,5-difluorophenyl)-6-oxopiperidine-1-carboxylate from Step C(1.53 g, 4.91 mmol) and iodoethane (0.993 mL, 12.3 mmol) in THF (15 mL)at −78° C. was added a 1 M solution of sodium bis(trimethylsilyl)amidein THF (10.8 mL, 10.8 mmol) dropwise over 15 min. The resulting mixturewas stirred at −78° C. for 10 min and at 0° C. for 2 h, then quenchedwith saturated aqueous NH₄Cl (50 mL) and extracted with EtOAc (3×50 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50,to give the title compound. MS: m/z=312 (M−C₄H₇).

Step E. (6S)-6-(3,5-Difluorophenyl)-3,3-diethylpiperidin-2-one

To a solution of tert-butyl(6S)-6-(3,5-difluorophenyl)-3,3-diethylpiperidin-2-one-1-carboxylatefrom Step D (1.22 g, 3.32 mmol) in CH₂Cl₂ (7 mL) at ambient temperaturewas added TFA (3 mL). After stirring for 1.5 h, the reaction mixture wasconcentrated in vacuo. The residue was partitioned between CH₂Cl₂ (30mL) and saturated NaHCO₃ (30 mL). The layers were separated and theaqueous layer was further extracted with CH₂Cl₂ (2×30 mL). The combinedorganics were dried over sodium sulfate, filtered and then concentratedin vacuo to provide the title compound, which could be used withoutfurther purification. MS: m/z=268 (M+1).

Step F.[(6S)-6-(3,5-Difluorophenyl)-3,3-diethyl-2-oxopiperidin-1-yl]acetic acid

To a stirred solution of(6S)-6-(3,5-difluorophenyl)-3,3-diethylpiperidin-2-one from Step E (850mg, 3.18 mmol) in THF (15 mL) at ambient temperature was added NaH (178mg of a 60% dispersion in oil, 4.45 mmol). After 15 min, methylbromoacetate (0.469 mL, 5.09 mmol) was added and the mixture was stirredfor 1 h. Sodium hydroxide (9.54 mL of a 1 M solution, 9.54 mmol) wasadded and the mixture stirred for an additional 16 h at 50° C. Thereaction mixture was poured onto 1 M HCl (30 mL) and extracted withEtOAc (3×30 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated in vacuo to provide the title compound, whichcould be used without further purification. MS: m/z=326 (M+1).

[(3R,6S)-6-(3,5-Difluorophenyl)-3-methyl-2-oxopiperidin-1-yl]acetic acidStep A. tert-Butyl(3R,6S)-6-(3,5-difluorophenyl)-3-methylpiperidin-2-one-1-carboxylate

To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (0.642 mL,0.642 mmol) at −78° C. was added dropwise a solution of tert-butyl(2S)-2-(3,5-difluorophenyl)-6-oxopiperidine-1-carboxylate (200 mg, 0.642mmol, described in Intermediate 26) in DME (10 mL) at −78° C. Theresulting mixture was stirred at −78° C. for 10 min then iodomethane(0.040 mL, 0.642 mmol) was added. After stirring at −78° C. for 30 minand at −30° C. for 30 min, the reaction mixture was cooled to −78° C.and quenched with saturated aqueous NH₄Cl (10 mL) and extracted withEtOAc (2×10 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0to 90:10. MS: m/z=270 (M−C₄H₇).

[(3R,6S)-6-(3,5-Difluorophenyl)-3-methyl-2-oxopiperidin-1-yl]acetic acid

Essentially following the procedures described for Intermediate 26, butusing tert-butyl(3R,6S)-6-(3,5-difluorophenyl)-3-methylpiperidin-2-one-1-carboxylate inplace of tert-butyl(6S)-6-(3,5-difluorophenyl)-3,3-diethylpiperidin-2-one-1-carboxylate,the title compound was prepared. MS: m/z=284 (M+1).

[(8R)-10-Oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetic acidhydrochloride Step A. Methyl1-[(2-oxo-2-phenylethyl)amino]cyclopentanecarboxylate

A mixture of methyl 1-aminocyclopentanecarboxylate hydrochloride (2.00g, 11.1 mmol, described in Intermediate 25), 2-bromoacetophenone (2.44g, 12.2 mmol), and NaHCO₃ (2.34 g, 27.9 mmol) in DMF (20 mL) was stirredat ambient temperature for 5 h. H₂O (25 mL) was added and the mixturewas extracted with EtOAc (2×75 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Theproduct-containing fractions were combined, adjusted to pH 10 byaddition of saturated aqueous Na₂CO₃ and extracted with EtOAc (2×75 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo to provide the title compound. MS: m/z=262 (M+1).

Step B. Ethyl [(8R)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate

To a stirred mixture of methyl1-[(2-oxo-2-phenylethyl)amino]cyclopentanecarboxylate from Step A (1.10g, 2.67 mmol) and glycine ethyl ester hydrochloride (881 mg, 6.31 mmol)in EtOH (10 mL) was added AcOH (0.72 mL, 12.6 mmol). The resultingmixture was stirred at ambient temperature for 5 min, then NaCNBH₃ (397mg, 6.31 mmol) was added. The reaction mixture was heated to 70° C. for3 h then allowed to cool. The reaction mixture was quenched withsaturated aqueous NaHCO₃ and then extracted with EtOAc (3×50 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by HPLC using areversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The product-containingfractions were combined, basified with saturated aqueous NaHCO₃, andextracted with EtOAc. The organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo to give the racemic product. Theenantiomers were separated by HPLC, using a Chiralcel OD column andeluting with hexane:EtOH—60:40. The first major peak to elute was ethyl[(8S)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate and the secondmajor peak to elute was ethyl[(8R)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate, the titlecompound. MS: m/z=317 (M+1).

Step C. [(8R)-10-Oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetic acidhydrochloride

To a solution of ethyl[(8R)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate from Step B(407 mg, 1.29 mmol) in THF (8 mL) and H₂O (2 mL) was added 1 N aqueousLiOH (1.54 mL, 1.54 mmol) and the resulting mixture was stirred atambient temperature for 4 h. The mixture was adjusted to pH 4 byaddition of 1 N HCl and concentrated to dryness in vacuo to give thetitle compound. MS: m/z=289 (M+1).

[(6R)-6-(3,5-Difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetic acidhydrochloride Step A. Methyl 2-amino-2-ethylbutanoate hydrochloride

A solution of 2-amino-2-ethylbutanoic acid (3.00 g, 22.9 mmol) in MeOH(200 mL) was saturated with HCl (g). The resulting mixture was heated atreflux for 24 h, during which time it was allowed to cool to ambienttemperature and was again saturated with HCl (g) twice. After 24 h atreflux, the cooled mixture was concentrated in vacuo to provide thetitle compound. MS: m/z=146 (M+1).

Step B. Methyl2-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}-2-ethylbutanoate

A mixture of methyl 2-amino-2-ethylbutanoate hydrochloride from Step A(2.10 g, 11.6 mmol), 3,5-difluorophenacyl bromide (2.99 g, 12.7 mmol),and NaHCO₃ (2.43 g, 28.9 mmol) in DMF (20 mL) was stirred at 45° C. for1 h, and at ambient temperature for 2 h. 1 N aqueous HCl (50 mL) wasadded and the mixture was extracted with EtOAc (75 mL) and this organicextract was discarded. The aqueous layer was adjusted to pH 10 byaddition of saturated aqueous Na₂CO₃ (150 mL) was added and the mixturewas extracted with EtOAc (3×75 mL). The combined organic layers weretreated with CF₃CO₂H (1.5 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by HPLC using areversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The product-containingfractions were combined, basified with saturated aqueous NaHCO₃, andextracted with EtOAc. The organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo to give the title compound. MS:m/z=300 (M+1).

Step C. Methyl[(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetate

To a stirred mixture of methyl2-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}-2-ethylbutanoate from StepB (475 mg, 1.59 mmol) and glycine ethyl ester hydrochloride (332 mg,2.38 mmol) in MeOH (5 mL) were added titanium(IV) isopropoxide (1.16 mL,3.97 mmol) and AcOH (0.273 mL, 4.76 mmol). The resulting mixture wasstirred at ambient temperature for 15 min, then NaCNBH₃ (150 mg, 2.38mmol) was added. The stirred reaction mixture was heated at 50° C. for18 h, then at 70° C. for 24 h, and allowed to cool. The mixture wasquenched with saturated aqueous NaHCO₃ and then extracted with EtOAc(2×30 mL). The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified byHPLC using a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The product-containingfractions were combined, basified with saturated aqueous NaHCO₃, andextracted with EtOAc. The organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo to give the racemic product. Theenantiomers were separated by HPLC, using a Chiralcel OD column andeluting with hexane:EtOH—60:40. The first major peak to elute was methyl[(6S)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetate andthe second major peak to elute was methyl[(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetate,the title compound. MS: m/z=341 (M+1).

Step D.[(6R)-6-(3,5-Difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetic acidhydrochloride

To a solution of methyl[(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetatefrom Step C (43 mg, 0.126 mmol) in THF (0.75 mL) and H₂O (0.25 mL) wasadded 1 N aqueous LiOH (0.139 mL, 0.139 mmol) and the resulting mixturewas stirred at ambient temperature for 1 h. The mixture was adjusted topH 4 by addition of 1 N HCl and concentrated to dryness in vacuo to givethe title compound. MS: m/z=327 (M+1).

[(8R)-8-(2-Bromo-3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]aceticacid Step A.[(8R)-8-(2-Bromo-3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]aceticacid

To a suspension of ethyl[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate(197 mg, 0.56 mmol, described in Intermediate 25) in boron trifluoridedihydrate (1.3 mL) was added N-bromosuccinimide (119 mg, 0.67 mmol) andthe resulting mixture was stirred at ambient temperature for 19 h, thenat 60° C. for 5 h. The mixture was diluted with H₂O (2 mL) and purifiedby HPLC using a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The product-containingfractions were combined and concentrated to dryness in vacuo to give thetitle compound as the TFA salt. MS: m/z=403 (M+1).

[(8R)-8-(4-Bromo-3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]aceticacid

This compound was generated as a byproduct in the reaction used toprepare Intermediate 30. The mixture was diluted with H₂O (2 mL) andpurified by HPLC using a reversed phase C18 column and eluting with agradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Theproduct-containing fractions were combined and concentrated to drynessin vacuo to give the title compound as the TFA salt. MS: m/z=403 (M+1).

Lithium[(8R)-6-(tert-butoxycarbonyl)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetateStep A. Methyl1-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}cyclopentanecarboxylate

A mixture of methyl 1-aminocyclopentanecarboxylate hydrochloride (10.0g, 55.7 mmol, described in Intermediate 25), 3,5-difluorophenacylbromide (14.4 g, 61.2 mmol), and Na₃PO₄ (22.8 g, 139 mmol) in DMF (100mL) was stirred at ambient temperature for 3.5 h. The reaction mixturewas acidified with 1 N aqueous HCl and the mixture was extracted withEtOAc (200 mL) and this organic extract was discarded. The aqueous layerwas adjusted to pH 8-9 by addition of saturated aqueous NaHCO₃ and themixture was extracted with EtOAc (3×250 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc—90:10 to 50:50, to give thetitle compound. MS: m/z=298 (M+1).

Step B. Ethyl[8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate

A mixture of methyl1-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}cyclopentanecarboxylate fromStep A (10.0 g, 33.6 mmol), glycine ethyl ester hydrochloride (46.9 g,336 mmol), and AcOH (5.78 mL, 101 mmol) in MeOH (300 mL) was stirred atambient temperature for 10 min. NaCNBH₃ (2.54 g, 40.4 mmol) was addedand the pH of the mixture was checked and adjusted to pH ˜5 as necessaryby addition of AcOH. The reaction mixture was heated to 50° C. for 18 hthen allowed to cool. The reaction mixture was carefully quenched withsaturated aqueous NaHCO₃ (250 mL) and then extracted with CH₂Cl₂ (3×200mL). The combined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with hexane:EtOAc—100:0 to 0:100, to give thetitle compound. MS: m/z=353 (M+1).

Step C. tert-Butyl(8R)-8-(3,5-difluorophenyl)-9-(2-ethoxy-2-oxoethyl)-10-oxo-6,9-diazaspiro[4.5]decane-6-carboxylate

A solution of ethyl[8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate fromStep B (3.00 g, 8.51 mmol), N,N-diisopropylethylamine (0.743 mL, 4.26mmol), and di-tert-butyl dicarbonate (9.29 g, 42.6 mmol) in acetonitrile(25 mL) was stirred at 60° C. for 6 h, then cooled and concentratedunder reduced pressure. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—95:5 to 50:50,to give the racemic product. The enantiomers were separated by HPLC,using a Chiralcel OD column and eluting withhexane:i-PrOH:Et₂NH—60:40:0.1. The first major peak to elute wastert-butyl(8S)-8-(3,5-difluorophenyl)-9-(2-ethoxy-2-oxoethyl)-10-oxo-6,9-diazaspiro[4.5]decane-6-carboxylateand the second major peak to elute was tert-butyl(8R)-8-(3,5-difluorophenyl)-9-(2-ethoxy-2-oxoethyl)-10-oxo-6,9-diazaspiro[4.5]decane-6-carboxylate,the title compound. MS: m/z=397 (M−C₄H₇).

Step D. Lithium[(8R)-6-(tert-butoxycarbonyl)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate

To a solution of tert-butyl(8R)-8-(3,5-difluorophenyl)-9-(2-ethoxy-2-oxoethyl)-10-oxo-6,9-diazaspiro[4.5]decane-6-carboxylatefrom Step C (50 mg, 0.11 mmol) in THF (0.75 mL) and H₂O (0.25 mL) wasadded 1 N aqueous LiOH (0.12 mL, 0.12 mmol) and the resulting mixturewas stirred at ambient temperature for 6 h. The mixture was adjusted topH 7 by addition of 1 N HCl and concentrated to dryness in vacuo to givethe title compound. MS: m/z=369 (M-C₄H₇).

Lithium[(3R)-1-(tert-butoxycarbonyl)-3-(3,5-difluorophenyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undec-4-yl]acetateStep A. Di-tert-butyl [1-(3,5-difluorophenyl)ethyl]imidodicarbonate

To a solution of [1-(3,5-difluorophenyl)ethyl]amine (10.0 g, 63.6 mmol)in CH₂Cl₂ (200 mL) at 0° C. was added di-tert-butyl dicarbonate (13.9 g,63.6 mmol) and the resulting mixture was stirred at ambient temperaturefor 18 h. The solvent was removed under reduced pressure. To the residuewas added di-tert-butyl dicarbonate (20.8 g, 95.4 mmol) and DMAP (7.78g, 63.6 mmol) and the reaction mixture was heated at 80° C. for 2 h. Themixture was allowed to cool and additional di-tert-butyl dicarbonate(69.4 g, 318 mmol) was added. The reaction mixture was heated at 80° C.for 2 h, allowed to cool, and concentrated in vacuo. The crude productwas purified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—98:2 to 90:10, to give the title compound. MS: m/z=421(M+Na+CH₃CN).

Step B. tert-Butyl2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propanoate

To a stirred suspension of potassium tert-butoxide in THF (300 mL) at−78° C. was added a solution of di-tert-butyl[1-(3,5-difluorophenyl)ethyl]imidodicarbonate from Step A (22.0 g, 61.6mmol) in THF (200 mL), dropwise, over 45 min. The reaction mixture wasallowed to warm to ambient temperature and stirring was continued for 3h. The reaction mixture was cooled to −78° C. and quenched with 1 Naqueous HCl (300 mL), warmed to 0° C., and poured into Et₂O (300 mL).The organic layer was extracted and the aqueous layer was extractedfurther with Et₂O (300 mL). The combined organic extracts were driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with hexane:EtOAc—95:5 to80:20, to give the title compound. MS: m/z=421 (M+Na+CH₃CN).

Step C. tert-Butyl [1-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate

To a stirred solution of tert-butyl2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propanoate fromStep B (2.00 g, 5.60 mmol) in THF (20 mL) at −78° C. was added LiAlH₄(5.60 mL of a 1 M solution in THF, 5.60 mmol), dropwise. The reactionmixture was stirred at −78° C. for 6 h, then quenched with EtOAc (5.6mL), then H₂O (15.6 mL), then 1 N aqueous NaOH (5.6 mL), then EtOAc (17mL). The reaction mixture was warmed to ambient temperature, stirred for1 h, filtered, and extracted with EtOAc (2×40 mL). The organic extractswere dried over Na₂SO₄, filtered, and concentrated in vacuo to affordthe title compound in sufficient purity for use in the next step. MS:m/z=186 (M−CO₂C₄H₇).

Step D. Methyl 1-aminocyclohexanecarboxylate hydrochloride

Essentially following the procedures described in Intermediate 25 formethyl 1-aminocyclopentanecarboxylate hydrochloride, but using1-aminocyclohexanecarboxylic acid in place of1-aminocyclopentanecarboxylic acid, the title compound was obtained. MS:m/z=158 (M+1).

Step E. Methyl1-{[2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propyl]amino}cyclohexanecarboxylate

A mixture of tert-butyl[1-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate from Step C (500mg, 1.75 mmol), methyl 1-aminocyclohexanecarboxylate hydrochloride fromStep D (1.38 g, 8.76 mmol), and AcOH (0.301 mL, 5.26 mmol) in MeOH (15mL) was stirred at ambient temperature for 30 min. NaCNBH₃ (165 mg, 2.63mmol) was added and the pH of the mixture was checked and adjusted to pH˜5 as necessary by addition of AcOH. The reaction mixture was stirred atambient temperature for 1 h, then quenched with saturated aqueous NaHCO₃(10 mL) and extracted with CH₂Cl₂ (2×50 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.The crude product was purified by silica gel chromatography, elutingwith hexane:EtOAc—100:0 to 80:20, to give the title compound. MS:m/z=427 (M+1).

Step F. Methyl1-{[2-amino-2-(3,5-difluorophenyl)propyl]amino}cyclohexanecarboxylate

A solution of methyl1-{[2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propyl]amino}cyclohexanecarboxylatefrom Step E (280 mg, 0.657 mmol) in EtOAc (5 mL) at 0° C. was saturatedwith HCl (g). The reaction mixture was aged at 0° C. for 30 min, thenpoured carefully into saturated aqueous NaHCO₃ (10 mL). The resultingmixture was extracted with EtOAc (2×15 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo togive the title compound. MS: m/z=327 (M+1).

Step G.(3R)-3-(3,5-Difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one

A solution of methyl1-{[2-amino-2-(3,5-difluorophenyl)propyl]amino}cyclohexanecarboxylatefrom Step F (205 mg, 0.628 mmol), and AcOH (0.36 mL, 6.28 mmol) inxylenes (5 mL) was heated at 80° C. for 3 h, allowed to cool, thenpoured into saturated aqueous NaHCO₃ (5 mL). The resulting mixture wasextracted with EtOAc (2×10 mL). The combined organic extracts were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude product was purified by silica gel chromatography, eluting with agradient of EtOAc:MeOH—100:0 to 92:8, to give the racemic product. Theenantiomers were separated by HPLC, using a ChiralPak AD column andeluting with hexane:EtOH:Et₂NH—40:60:0.1. The first major peak to elutewas(3R)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one,the title compound, and the second major peak to elute was(3S)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one.MS: m/z=295 (M+1).

Step H. tert-Butyl(3R)-3-(3,5-difluorophenyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylate

A solution of(3R)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-onefrom Step G (90 mg, 0.306 mmol), N,N-diisopropylethylamine (0.027 mL,0.153 mmol), and di-tert-butyl dicarbonate (667 mg, 3.06 mmol) inacetonitrile (2 mL) was stirred at 60° C. for 8 h, then cooled andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5to 50:50, to give the title compound. MS: m/z=339 (M−C₄H₇).

Step I. tert-Butyl(3R)-3-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoethyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylate

To a stirred solution of tert-butyl(3R)-3-(3,5-difluorophenyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylatefrom Step H (60 mg, 0.152 mmol) in THF (0.5 mL) at 0° C. was added NaH(12 mg of a 60% dispersion in oil, 0.30 mmol). After 5 min, ethylbromoacetate (437 mg, 2.62 mmol) was added and the mixture was allowedto warm to ambient temperature and stirring was continued for 1 h.Saturated aqueous NaHCO₃ (2 mL) was added and the mixture was extractedwith EtOAc (2×5 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5to 60:40, to give the title compound. MS: m/z=425 (M−C₄H₇).

Step J. Lithium[(3R)-1-(tert-butoxycarbonyl)-3-(3,5-difluorophenyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undec-4-yl]acetate

To a solution of tert-butyl(3R)-3-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoethyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylatefrom Step I (65 mg, 0.135 mmol) in THF (1.5 mL) and H₂O (0.5 mL) wasadded 1 N aqueous LiOH (0.14 mL, 0.14 mmol) and the resulting mixturewas stirred at ambient temperature for 1 h. The mixture was adjusted topH 7 by addition of 1 N HCl and concentrated to dryness in vacuo to givethe title compound. MS: m/z=397 (M−C₄H₇).

[(5″R)-1′-(tert-Butoxycarbonyl)-4″,6″-difluoro-3′-oxo-2″,3″-dihydro-4′H-dispiro[cyclopentane-1,2′-piperazine-5′,1″-inden]-4′-yl]aceticacid Step A.4′,6′-Difluoro-2′,3′-dihydro-2H,5H-spiro[imidazolidine-4,1′-indene]-2,5-dione

A mixture of 4,6-difluoroindan-1-one [Musso et al. (2003) J. Med. Chem.,46, 399-408] (14.5 g, 86 mmol), NaCN (12.9 g, 262 mmol), and (NH₄)₂CO₃(16.8 g, 175 mmol) in H₂O (150 mL) and EtOH (150 mL) was heated at 70°C. for 3 h. Additional (NH₄)₂CO₃ (16.8 g, 175 mmol) was added andheating at 70° C. was continued for 4 h. The mixture was concentrated todryness under reduced pressure. To the residue was added H₂O (200 mL)and the precipitate was isolated by filtration, washed with H₂O, anddried to give the title compound. MS: m/z=280 (M+1+CH₃CN).

Step B. 1-Amino-4,6-difluoroindane-1-carboxylic acid hydrochloride

A mixture of4′,6′-difluoro-2′,3′-dihydro-2H,5H-spiro[imidazolidine-4,1′-indene]-2,5-dionefrom Step A (16.7 g, 70.1 mmol) and conc. HCl (90 mL) in a high pressurereactor was heated at 180° C. for 5 h. The mixture was cooled to 0° C.,vented carefully, and concentrated to dryness in vacuo to afford thetitle compound. MS: m/z=214 (M+1).

Step C. Methyl 1-amino-4,6-difluoroindane-1-carboxylate hydrochloride

A solution of 1-amino-4,6-difluoroindane-1-carboxylic acid hydrochloride(2.00 g, 15.5 mmol) in MeOH (100 mL) was saturated with HCl (g). Theresulting mixture was heated at reflux for 20 h and concentrated invacuo to provide the title compound. MS: m/z=228 (M+1).

Step D. Methyl1-[(tert-butoxycarbonyl)amino]-4,6-difluoroindane-1-carboxylate

A solution of methyl 1-amino-4,6-difluoroindane-1-carboxylatehydrochloride from Step C (3.82 g, 14.5 mmol), N,N-diisopropylethylamine(5.62 g, 43.5 mmol), and di-tert-butyl dicarbonate (15.8 g, 72.5 mmol)in acetonitrile (40 mL) was stirred at 60° C. for 3 h, then cooled andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0to 40:60, to give the title compound. MS: m/z=228 (M−CO₂C₄H₇).

Step E. tert-Butyl[4,6-difluoro-1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl]carbamate

To a stirred solution of methyl1-[(tert-butoxycarbonyl)amino]-4,6-difluoroindane-1-carboxylate fromStep D (2.80 g, 8.55 mmol) in THF (30 mL) at −78° C. was added LiAlH₄(18.0 mL of a 1 M solution in THF, 18.0 mmol), dropwise, over 30 min.The reaction mixture was stirred at −78° C. for 2 h, then quenched withH₂O (1 mL), then 1 N aqueous NaOH (2 mL), then H₂O (2 mL), then EtOAc (2mL). The reaction mixture was warmed to ambient temperature, saturatedaqueous NaHCO₃ (150 mL) was added, and the mixture was extracted withEtOAc (200 mL). The organic extract was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50,to give the title compound. MS: m/z=244 (M−C₄H₇).

Step F. tert-Butyl(4,6-difluoro-1-formyl-2,3-dihydro-1H-inden-1-yl)carbamate

To a stirred solution of oxalyl chloride (0.91 mL, 10.4 mmol) in CH₂Cl₂(40 mL) at −78° C. was added DMSO (1.48 mL, 20.9 mmol), dropwise, over 5min. The reaction mixture was stirred for 30 min, during which time itwarmed to −60° C., then a solution of tert-butyl[4,6-difluoro-1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl]carbamate fromStep E (2.08 g, 6.95 mmol) in CH₂Cl₂ (22 mL) was added, dropwise, over30 min. During the addition, the reaction temperature rose to −45° C.and it was stirred at this temperature for an additional 15 min. To theresulting mixture was added N,N-diisopropylethylamine (7.28 mL, 41.7mmol), dropwise, over 2 min. The mixture was allowed to warm to 0° C.,stirred for 15 min then poured into ice (60 mL) and 1 N aqueous HCl (30mL). The resulting mixture was extracted with CH₂Cl₂ (2×100 mL). Thecombined organic extracts were washed with H₂O (30 mL), then brine (50mL), then dried over Na₂SO₄, filtered, and concentrated in vacuo to givethe title compound. MS: m/z=224 (M−OC₄H₉).

Step G. Methyl1-[({1-[(tert-butoxycarbonyl)amino]-4,6-difluoro-2,3-dihydro-1H-inden-1-yl}methyl)amino]cyclopentanecarboxylate

A mixture of tert-butyl(4,6-difluoro-1-formyl-2,3-dihydro-1H-inden-1-yl)carbamate from Step F(890 mg, 2.99 mmol), methyl 1-aminocyclopentanecarboxylate (4.25 g, 29.7mmol, described in Intermediate 25), and AcOH (2.10 mL, 36.7 mmol) inMeOH (32 mL) was stirred at ambient temperature for 20 min. NaCNBH₃ (405mg, 6.44 mmol) was added and the pH of the mixture was checked andadjusted to pH ˜5 as necessary by addition of AcOH. The reaction mixturewas stirred at ambient temperature for 23 h, then quenched withsaturated aqueous NaHCO₃ (80 mL) and extracted with EtOAc (200 mL). Theorganic extract was washed with H₂O (50 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with hexane:EtOAc—100:0 to 30:70, togive the title compound. MS: m/z=425 (M+1).

Step H. Methyl1-{[(1-amino-4,6-difluoro-2,3-dihydro-1H-inden-1-yl)methyl]amino}cyclopentanecarboxylatehydrochloride

A solution of methyl1-[({1-[(tert-butoxycarbonyl)amino]-4,6-difluoro-2,3-dihydro-1H-inden-1-yl}methyl)amino]cyclopentanecarboxylatefrom Step G (753 mg, 1.77 mmol) in EtOAc (40 mL) at 0° C. was saturatedwith HCl (g). The reaction mixture was aged at 0° C. for 45 min thenconcentrated in vacuo to give the title compound. MS: m/z=325 (M+1).

Step I.4″,6″-Difluoro-2″,3″-dihydro-3′H-dispiro[cyclopentane-1,2′-piperazine-5′,1″-inden]-3′-one

A solution of methyl1-{[(1-amino-4,6-difluoro-2,3-dihydro-1H-inden-1-yl)methyl]amino}cyclopentanecarboxylatehydrochloride from Step H (741 mg, 2.05 mmol), and AcOH (5.0 mL, 6.28mmol) in xylenes (50 mL) was heated at 150° C. for 24 h, allowed tocool, and concentrated to dryness under reduced pressure. The residuewas partitioned between saturated aqueous NaHCO₃ (80 mL) and EtOAc (100mL). The organic extract was washed with H₂O (60 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give the titlecompound. MS: m/z=293 (M+1).

Step J. tert-Butyl(5″R)-4″,6″-difluoro-3′-oxo-2″,3″-dihydro-1′H-dispiro[cyclopentane-1,2′-piperazine-5′,1″-indene]-1′-carboxylate

A solution of4″,6″-difluoro-2″,3″-dihydro-3′H-dispiro[cyclopentane-1,2′-piperazine-5′,1″-inden]-3′-onefrom Step I (453 mg, 1.55 mmol), N,N-diisopropylethylamine (0.135 mL,0.78 mmol), and di-tert-butyl dicarbonate (3.45 g, 15.8 mmol) inacetonitrile (6 mL) was stirred at 50° C. for 18 h. The reaction mixturewas partitioned between saturated aqueous NaHCO₃ (40 mL) and EtOAc (60mL). The organic extract was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0to 50:50, to give the racemic product. The enantiomers were separated byHPLC, using a ChiralPak AD column and eluting withhexane:EtOH:Et₂NH—40:60:0.1. The first major peak to elute wastert-butyl(5″R)-4″,6″-difluoro-3′-oxo-2″,3″-dihydro-1′H-dispiro[cyclopentane-1,2′-piperazine-5′,1″-indene]-1′-carboxylate,the title compound, and the second major peak to elute was tert-butyl(5″S)-4″,6″-difluoro-3′-oxo-2″,3″-dihydro-1′H-dispiro[cyclopentane-1,2′-piperazine-5′,1″-indene]-1′-carboxylate.MS: m/z=337 (M−C₄H₇).

Step K. tert-Butyl(5″R)-4′-(2-ethoxy-2-oxoethyl)-4″,6″-difluoro-3′-oxo-2″,3″-dihydro-1′H-dispiro[cyclopentane-1,2′-piperazine-5′,1″-indene]-1′-carboxylate

To a stirred solution of tert-butyl(5″R)-4″,6″-difluoro-3′-oxo-2″,3″-dihydro-1′H-dispiro[cyclopentane-1,2′-piperazine-5′,1″-indene]-1′-carboxylatefrom Step J (217 mg, 0.553 mmol) in THF (4 mL) at ambient temperaturewas added NaH (44 mg of a 60% dispersion in oil, 1.11 mmol). After 15min, ethyl bromoacetate (185 mg, 1.11 mmol) was added and the mixturewas allowed to warm to ambient temperature and stirring was continuedfor 3 h. Saturated aqueous NaHCO₃ (25 mL) was added and the mixture wasextracted with EtOAc (2×30 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS:m/z=479 (M+1).

Step L.[(5″R)-1′-(tert-Butoxycarbonyl)-4″,6″-difluoro-3′-oxo-2″,3″-dihydro-4′H-dispiro[cyclopentane-1,2′-piperazine-5′,1″-inden]-4′-yl]aceticacid

To a solution of tert-butyl(5″R)-4′-(2-ethoxy-2-oxoethyl)-4″,6″-difluoro-3′-oxo-2″,3″-dihydro-1′H-dispiro[cyclopentane-1,2′-piperazine-5′,1″-indene]-1′-carboxylatefrom Step K (258 mg, 0.539 mmol) in THF (3 mL) was added 1 N aqueousLiOH (0.65 mL, 0.65 mmol) and the resulting mixture was stirred atambient temperature for 20 h. To the reaction mixture was added THF (3mL), EtOH (0.2 mL), and 1 N aqueous LiOH (0.20 mL, 0.20 mmol) and theresulting mixture was stirred at ambient temperature for 16 h. Themixture was acidified by addition of 1 N aqueous HCl (0.9 mL, 0.9 mmol)and concentrated to dryness in vacuo to give the title compound. MS:m/z=451 (M+1).

(±)-[4′-(tert-Butoxycarbonyl)-4,6-difluoro-5′,5′-dimethyl-6′-oxo-2,3-dihydro-1′H-spiro[indene-1,2′-piperazin]-1′-yl]aceticacid

Essentially following the procedures described in Intermediate 34, butusing methyl α-aminoisobutyrate in place of methyl1-aminocyclopentanecarboxylate, the title compound was obtained. MS:m/z=425 (M+1).

[4-(tert-Butoxycarbonyl)-3,3-dimethyl-2-oxo-1,4-diazaspiro[5.6]dodec-1-yl]aceticacid

Essentially following the procedures described in Intermediate 34, butusing methyl α-aminoisobutyrate in place of methyl1-aminocyclopentanecarboxylate, and using methyl1-aminocycloheptanecarboxylate hydrochloride in place of methyl1-amino-4,6-difluoroindane-1-carboxylate hydrochloride, the titlecompound was obtained. MS: m/z=369 (M+1).

[(3S)-3-(3,5-Difluorophenyl)-1-oxo-9-oxa-2-azaspiro[5.5]undec-2-yl]aceticacid

Essentially following the procedures described in Intermediate 26, butusing 2-iodoethyl ether in place of iodoethane, the title compound wasobtained. MS: m/z=340 (M+1).

Methyl 1-{[(3S)-3-amino-3-phenylpropyl]amino}cyclopentanecarboxylatebis-hydrochloride Step A. Ethyl(3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate

To a solution of (S)-3-amino-3-phenylpropanoic acid ethyl esterhydrochloride (2.50 g, 10.9 mmol) and Boc-anhydride (2.38 g, 10.9 mmol)in CH₂Cl₂ (16.3 mL) was slowly added triethylamine (3.03 mL, 21.8 mmol).After 4.5 hours, the reaction mixture was applied to the top of a silicagel column, and following elution with a gradient of EtOAc:hexanes—5:95to 40:60 the title compound was obtained. MS: m/z=294 (M+1).

Step B. tert-Butyl [(1S)-3-oxo-1-phenylpropyl]carbamate

To a dry, cooled (−78° C.) solution of ethyl(3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate from Step A (1.00g, 3.41 mmol) was added a solution of DiBAl—H (6.82 mL, 6.82 mmol, 1 Min CH₂Cl₂) slowly over 30 min. After an additional 30 min of stirring at−78° C., the reaction was quenched by the rapid addition of saturatedaqueous Rochelle's salt (32 mL). The cooling bath was then removed andthe reaction was allowed to rapidly stir until a noticeable decrease inthe amount of emulsion was observed. The layers were separated and theaqueous layer was extracted with CH₂Cl₂ (2×30 mL). Combined organicswere dried over sodium sulfate, filtered and concentrated in vacuo togive an oil. This oil was purified by silica gel chromatography, elutingwith a gradient of EtOAc:hexanes 5:95 to 40:60, to give the titlecompound. MS: m/z=150 (M−CO₂C₄H₇).

Step C. Methyl1-({(3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}amino)cyclopentanecarboxylate

To a solution of tert-butyl [(1S)-3-oxo-1-phenylpropyl]carbamate fromStep B (0.820 g, 3.29 mmol) and methyl 1-aminocyclopentanecarboxylatehydrochloride (0.591 g, 3.29 mmol) in chloroform (33 mL) was addedHunig's base (0.574 mL, 3.29 mmol). After stirring at ambienttemperature for 20 min, NaHB(OAc)₃ (1.74 g, 8.22 mmol) was added as asolid. Upon completion of the reaction, saturated aqueous NaHCO₃ (3 mL)was added and the mixture was allowed to stir for at least 2 h. Water (5mL) and additional saturated NaHCO₃ (3 mL) was then added to form twolayers. The aqueous layer was extracted once with chloroform (50 mL).The combined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo to give an oil. This oil was purified by silicagel chromatography, eluting with a gradient of MeOH:DCM 1:99 to 6:94, togive the title compound. MS: m/z=377 (M+1).

Step D. Methyl1-{[(3S)-3-amino-3-phenylpropyl]amino}cyclopentanecarboxylatebis-hydrochloride

To a cooled (0° C.) solution of methyl1-({(3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}amino)cyclopentanecarboxylatefrom Step C (0.920 g, 2.44 mmol) in MeOH (49 mL) was added excessanhydrous hydrogen chloride gas. After 30 min the solution was purgedwith dry nitrogen for about 40 min. The solvent was then removed invacuo to provide a solid/oil mix. Additional MeOH (50 mL) was then addedand subsequently removed in vacuo to provide the title compound. MS:m/z=277 (M+1).

[(4aR,9aS)-3-Oxo-2,3,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-4(4aH)-yl]aceticacid Step A.2-Chloro-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide

To a mixture of (1R,2S)-1-amino-2-indanol (500 mg, 3.35 mmol) andtriethylamine (0.51 mL, 3.69 mmol) in anhydrous CH₂Cl₂ at 0° C. wasadded chloroacetyl chloride (0.295 mL, 3.69 mmol) dropwise. Theresulting mixture was stirred for 30 min, quenched with saturatedaqueous NaHCO₃ (15 mL) and then extracted with EtOAc (2×75 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc 70:30 to 0:100,to give the title compound. MS: m/z=226 (M+1).

Step B. (4aR,9aS)-4,4a,9,9a-Tetrahydroindeno[2,1-b][1,4]oxazin-3(2H)-one

To a stirred mixture of2-chloro-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide fromStep A (780 mg, 3.46 mmol) in anhydrous THF (75 mL) at 0° C. was addedNaH (498 mg of a 60% dispersion in oil, 12.4 mmol). The resultingmixture was stirred for 3 h, quenched with saturated aqueous NaHCO₃ (20mL) and then extracted with EtOAc (3×50 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated in vacuo to give thetitle compound. MS: m/z=190 (M+1).

Step C. Ethyl[(4aR,9aS)-3-oxo-2,3,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-4(4aH)-yl]acetate

To a solution of(4aR,9aS)-4,4a,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-3(2H)-one fromStep B (600 mg, 3.17 mmol) in DMF (15 mL) at 0° C. was added NaH (228 mgof a 60% dispersion in oil, 5.71 mmol) and the resulting mixture wasstirred for 10 min. Ethyl bromoacetate (0.288 mL, 3.5 mmol) was addedand the reaction mixture was stirred for 18 h. The reaction mixture wasquenched with saturated aqueous NaHCO₃ (10 mL) and then extracted withEtOAc (2×40 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc 80:20to 0:100, to give the title compound. MS: m/z=276 (M+1)

Step D.[(4aR,9aS)-3-Oxo-2,3,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-4(4aH)-yl]aceticacid

To a solution of ethyl[(4aR,9aS)-3-oxo-2,3,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-4(4aH)-yl]acetatefrom Step C (480 mg, 1.74 mmol) in THF (7.5 mL) and H₂O (2.5 mL) wasadded 1 N aqueous LiOH (2.1 mL, 2.09 mmol) and the resulting mixture wasstirred at ambient temperature for 4 h. The mixture was adjusted to pH 4by addition of 1 N HCl and concentrated to dryness in vacuo to give thetitle compound. MS: m/z=248 (M+1).

1-(2-Oxo-5-phenylpiperazin-1-yl)cyclopropanecarboxylic acid Step A.Ethyl 1-[(2-oxo-2-phenylethyl)amino]cyclopropanecarboxylate

A mixture of ethyl 1-aminocyclopropanecarboxylate hydrochloride (1.0 g,7.74 mmol), 2-bromoacetophenone (3.08 g, 15.5 mmol), and NaHCO₃ (1.30 g,15.5 mmol) in DMF (20 mL) was stirred at ambient temperature for 18 h.H₂O (20 mL) was added and the mixture was extracted with EtOAc (2×75mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by HPLC using areversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The product-containingfractions were combined, adjusted to pH 10 by addition of saturatedaqueous Na₂CO₃ and extracted with EtOAc (2×75 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated in vacuo toprovide the title compound. MS: m/z=248 (M+1).

Step B. Ethyl 1-(2-oxo-5-phenylcyclohexyl)cyclopropanecarboxylate

To a stirred mixture of ethyl1-[(2-oxo-2-phenylethyl)amino]cyclopropanecarboxylate from Step A (500mg, 2.02 mmol) and glycine ethyl ester hydrochloride (339 mg, 2.43 mmol)in MeOH (5 mL) was added AcOH (0.58 mL, 10.1 mmol). The resultingmixture was stirred at ambient temperature for 10 min, then NaCNBH₃ (152mg, 2.43 mmol) was added. The reaction mixture was heated to 50° C. for6 h then allowed to cool. The reaction mixture was quenched withsaturated aqueous NaHCO₃ and then extracted with EtOAc (3×40 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by HPLC using areversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The product-containingfractions were combined and concentrated in vacuo to give the titledcompound as a colorless oil. MS: m/z=289 (M+1).

Step C. 1-(2-Oxo-5-phenylpiperazin-1-yl)cyclopropanecarboxylic acid

To a solution of ethyl1-(2-oxo-5-phenylcyclohexyl)cyclopropanecarboxylate from Step B (35 mg,0.121 mmol) in THF (0.75 mL) and H₂O (0.25 mL) was added 1 N aqueousLiOH (0.146 mL, 0.146 mmol) and the resulting mixture was stirred for 18h. The mixture was adjusted to pH 4 by addition of 1 N HCl andconcentrated to dryness in vacuo to give the title compound. MS: m/z=261(M+1).

3-Amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,isomer A Step A.(±)-1′-{[2-(Trimethylsilyl)ethoxy]methyl}-3H-spiro[cyclopentane-1,3′-pyrrolo[2,3-b]pyridine]-2′,3(1′H)-dione

To a solution of1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(2.50 g, 9.46 mmol, described in Intermediate 7) and cesium carbonate(6.78 g, 20.8 mmol) in DMF (45 mL) was added dropwise a solution of1,4-dibromobutan-2-one [Meijere et al. (2001) Eur. J. Org. Chem. 20,3789-3795] (1.59 g, 12.3 mmol) in DMF (45 mL). After 68 h, the mixturewas partitioned between Et₂O (200 mL) and H₂O (200 mL). The organiclayer was separated and the aqueous layer was further extracted withEt₂O (2×100 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0to 75:25, to give the title compound. MS: m/z=333 (M+1).

Step B.(±)-3-Nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A mixture of(±)-1′-{[2-(trimethylsilyl)ethoxy]methyl}-3H-spiro[cyclopentane-1,3′-pyrrolo[2,3-b]pyridine]-2′,3(1′H)-dionefrom Step A (230 mg, 0.692 mmol) and1-methyl-3,5-dinitropyridin-2(1H)-one [Tohda et al. (1990) Bull. Chem.Soc. Japan 63, 2820-2827] (173 mg, 0.869 mmol) in 2 M ammonia in MeOH(3.5 mL) was heated to reflux for 18 h. The mixture was concentrated invacuo and purified by silica gel chromatography, eluting with a gradientof hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=413(M+1).

Step C.(±)-3-Amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′pyrrolo[2,3-b]pyridin]-2(1′H)-one

A mixture of 10% Pd/C (20 mg) and(±)-3-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step B (117 mg, 0.284 mmol) was stirred vigorously in MeOH (5 mL)under an atmosphere of hydrogen (ca. 1 atm). After 4.5 h, the mixturewas filtered through a pad of Celite, washing extensively with MeOH, andthe filtrate was concentrated in vacuo to give the title compound. MS:m/z=383 (M+1).

Step D.3-Amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,isomer A

A solution of(±)-3-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step C (117 mg, 0.306 mmol) in MeOH (5 mL) was saturated with HCl(g). The mixture was stirred for 30 min and then concentrated in vacuo.The residue was dissolved in MeOH (3 mL) and treated withethylenediamine (0.020 mL, 0.306 mmol) and 10 N sodium hydroxide toadjust the mixture to pH 10. After 1 h, the reaction mixture waspurified directly by HPLC using a reversed phase C18 column and elutingwith a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1.Lyophilization provided the racemic title compound as the TFA salt. Theenantiomers were resolved by HPLC, utilizing a ChiralPak AD column andeluting with EtOH. The first major peak to elute was3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,isomer A, the title compound, and the second major peak to elute was3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,isomer B. MS: m/z=253 (M+1).

3-Amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,isomer A Step A. 4,5-Bis(hydroxymethyl)pyridine-2-carbonitrile

To a solution of dimethyl 6-cyanopyridine-3,4-dicarboxylate [Hashimotoet al. (1997) Heterocycles 46, 581] (2.00 g, 9.08 mmol) in EtOH (50 mL)was added lithium borohydride (4.54 mL of a 2 M solution in THF, 9.08mmol) dropwise. The reaction mixture was stirred at ambient temperaturefor 3 h, and then cooled to 0° C. Saturated aqueous NaHCO₃ (20 mL) wasadded slowly and the quenched mixture was extracted with EtOAc (9×100mL). The combined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 85:15,to give the title compound. MS: m/z=165 (M+1).

Step B. 4,5-Bis(bromomethyl)pyridine-2-carbonitrile

To a solution of 4,5-bis(hydroxymethyl)pyridine-2-carbonitrile from StepA (750 mg, 4.57 mmol) in THF (15 mL) was added phosphorus tribromide(1.61 g, 5.94 mmol) in THF (5 mL) dropwise. The reaction mixture wasstirred at ambient temperature for 2 h, and then cooled to 0° C.Saturated aqueous NaHCO₃ (5 mL) was added slowly and the quenchedmixture was extracted with CHCl₃ (2×30 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.The crude product was purified by silica gel chromatography, elutingwith a gradient of hexane:EtOAc—100:0 to 25:75, to give the titlecompound. MS: m/z=291 (M+1).

Step C.(±)-2′-Oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carbonitrile

To a solution of 4,5-bis(bromomethyl)pyridine-2-carbonitrile from Step B(2.56 g, 8.83 mmol) and 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one[Marfat & Carta (1987) Tetrahedron Lett. 28, 4027] (1.18 g, 8.83 mmol)in THF (120 mL) and H₂O (60 mL) was added lithium hydroxide monohydrate(1.11 g, 26.5 mmol). After 20 min, the reaction mixture was poured ontowater (100 mL) and extracted with EtOAc (3×100 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.The crude product was purified by silica gel chromatography, elutingwith a gradient of CH₂Cl₂:MeOH:NH₄OH—100:0:0 to 95:5:1, to give thetitle compound. MS: m/z=263 (M+1).

Step D. (±)-Sodium2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate

To a solution of(±)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carbonitrilefrom Step C (1.53 g, 5.83 mmol) in EtOH (20 mL) was added 5 M aqueousNaOH (3.50 mL). The mixture was heated at reflux for 72 h, withadditional 5 M aqueous NaOH (2.00 mL) added at 6 h. The reaction mixturewas allowed to cool and was concentrated to dryness in vacuo to affordthe title compound in sufficient purity for use in subsequent steps. MS:m/z=282 (M+1).

Step E. (±)-tert-Butyl(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)carbamate

To a suspension of (±)-sodiumtetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylatefrom Step D (1.64 g, 5.83 mmol) and triethylamine (1.62 mL, 11.7 mmol)in tert-butanol (50 mL) was added diphenylphosphoryl azide (1.89 mL,8.75 mmol) and the mixture was heated at reflux for 72 h. Additionaldiphenylphosphoryl azide (1.89 mL, 8.75 mmol) was added after 24 h and56 h. The reaction mixture was concentrated in vacuo and thenpartitioned between CH₂Cl₂ (75 mL) and saturated NaHCO₃ (100 mL). Theorganic layer was separated and the aqueous layer was further extractedwith CH₂Cl₂ (2×50 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH:NH₄OH—100:0:0 to 95:5:1, to give the title compound. MS:m/z=353 (M+1).

Step F.3-Amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,isomer A

A solution of (±)-tert-butyl(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)carbamatefrom Step E (1.39 g, 3.94 mmol) was stirred in CH₂Cl₂ (10 mL) and TFA (3mL) for 18 h and then concentrated in vacuo to provide the racemic titlecompound as the TFA salt. The enantiomers were resolved by HPLC,utilizing a ChiralPak AD column and eluting with MeOH. The first majorpeak to elute was3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,isomer A, the title compound, and the second major peak to elute was3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,isomer B. MS: m/z=253 (M+1).

(±)-2-Amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-oneStep A. Dimethyl 6-cyanopyridine-2,3-dicarboxylate

To a solution of dimethylpyridine-2,3-dicarboxylate 1-oxide [Niiyami etal. (2002) Bioorg. Med. Chem. Lett. 12, 3041] (15.3 g, 72.5 mmol) andtrimethylsilyl cyanide (15.7 mL, 117 mmol) in DME (161 mL) was addeddimethylcarbamoyl chloride (10.5 mL, 114 mmol). The reaction mixture washeated at reflux for 72 h, and then cooled to 0° C. Saturated aqueousNaHCO₃ (800 mL) was added slowly and the quenched mixture was extractedwith EtOAc (2×1 L). The combined organic extracts were washed with brine(200 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS:m/z=221 (M+1).

Step B. 5,6-Bis(hydroxymethyl)pyridine-2-carbonitrile

To a solution of dimethyl 6-cyanopyridine-2,3-dicarboxylate from Step A(13.0 g, 59.0 mmol) in EtOH (295 mL) was added lithium borohydride (29.5mL of a 2 M solution in THF, 59.0 mmol) dropwise. The reaction mixturewas stirred at ambient temperature for 4 h, and then cooled to 0° C.Saturated aqueous NaHCO₃ (200 mL) was added slowly and the quenchedmixture was extracted with EtOAc (9×100 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.The crude product was purified by silica gel chromatography, elutingwith a gradient of CH₂Cl₂:MeOH—100:0 to 85:15, to give the titlecompound. MS: m/z=165 (M+1).

Step C. 5,6-Bis(bromomethyl)pyridine-2-carbonitrile

To a solution of 5,6-bis(hydroxymethyl)pyridine-2-carbonitrile from StepB (2.50 g, 15.2 mmol) in THF (76 mL) was added phosphorus tribromide(5.36 g, 19.8 mmol) in THF (20 mL) dropwise. The reaction mixture wasstirred at ambient temperature for 2 h, and then cooled to 0° C.Saturated aqueous NaHCO₃ (20 mL) was added slowly and the quenchedmixture was extracted with CH₂Cl₂ (2×200 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.The crude product was purified by silica gel chromatography, elutingwith a gradient of hexane:EtOAc—100:0 to 30:70, to give the titlecompound. MS: m/z=291 (M+1).

Step D.(±)-2′-Oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-2-carbonitrile

To a solution of 5,6-bis(bromomethyl)pyridine-2-carbonitrile from Step C(1.80 g, 6.21 mmol) and1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(1.64 g, 6.21 mmol, described in Intermediate 7) in DMF (207 mL) wasadded cesium carbonate (6.07 g, 18.6 mmol), portionwise, over 5 min.After 18 h, the mixture was partitioned between CH₂Cl₂ (100 mL),saturated aqueous NaHCO₃ (100 mL) and brine (200 mL). The organic layerwas removed and the aqueous layer was extracted further with CH₂Cl₂(2×100 mL). The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0to 10:90, to give the title compound. MS: m/z=393 (M+1).

Step E.(±)-2′-Oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-2-carboxylicacid

To a solution of(±)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-2-carbonitrilefrom Step D (690 mg, 1.76 mmol) in THF (5 mL) was added 3 N aqueous HCl(36 mL). The mixture was heated at reflux for 18 h, allowed to cool andconcentrated to dryness in vacuo. The reaction mixture was dissolved inwater (12 mL) and purified directly by HPLC using a reversed phase C18column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—95:5:0.1 to5:95:0.1. Lyophilization of the product-containing fractions providedthe title compound. MS: m/z=282 (M+1).

Step F. (±)-tert-Butyl(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2-yl)carbamate

To a suspension of(±)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-2-carboxylicacid from Step E (224 mg, 0.796 mmol) and triethylamine (0.333 mL, 2.39mmol) in tert-butanol (5 mL) was added diphenylphosphoryl azide (0.258mL, 1.20 mmol) and the mixture was heated at reflux for 1 h. Thereaction mixture was concentrated in vacuo and then partitioned betweenCH₂Cl₂ (20 mL) and saturated NaHCO₃ (20 mL). The organic layer wasseparated and the aqueous layer was further extracted with CH₂Cl₂ (2×20mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH:NH₄OH—100:0:0 to95:5:1, to give the title compound. MS: m/z=353 (M+1).

Step G.(±)-2-Amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A solution of (±)-tert-butyl(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2-yl)carbamatefrom Step F (147 mg, 0.417 mmol) was stirred in CH₂Cl₂ (6 mL) and TFA (1mL) for 3 h and then concentrated in vacuo to provide the title compoundas the TFA salt. MS: m/z=253 (M+1).

[(5R,8S)-1-[(Benzyloxy)carbonyl]-8-(3,5-difluorophenyl)-6-oxo-1,7-diazaspiro[4.5]dec-7-yl]aceticacid Step A. 1-Benzyl 2-methyl(2R)-2-(3-oxopropyl)pyrrolidine-1,2-dicarboxylate

To a solution of DMSO (5.11 mL, 72.1 mmol) in CH₂Cl₂ (25 mL) at −78° C.was added a solution of oxalyl chloride (3.15 mL, 36.0 mmol) in CH₂Cl₂(25 mL) dropwise. After 10 min of additional stirring, a solution of1-benzyl 2-methyl (2R)-2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate[Cox and Lectka (1998) J. Am. Chem. Soc. 120, 10660-10668] (7.72 g, 24.0mmol) in CH₂Cl₂ (50 mL) at −78° C. was added dropwise. After stirringfor an additional 1 h, triethylamine (16.7 mL, 120 mmol) was addedslowly. The reaction mixture was stirred for 1 h at −78° C. and 2.5 h atambient temperature. Water (100 mL) was added slowly and the quenchedmixture was extracted with EtOAc (3×100 mL). The combined organicextracts were washed with 10% HCl (50 mL) and brine (50 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—90:10 to 0:100, to give the title compound. MS: m/z=320(M+1).

Step B. 1-Benzyl 2-methyl(2R)-2-((3E)-3-{[(S)-tert-butylsulfinyl]imino}propyl)pyrrolidine-1,2-dicarboxylate

To a mixture of 1-benzyl 2-methyl(2R)-2-(3-oxopropyl)pyrrolidine-1,2-dicarboxylate from Step A (1.69 g,5.29 mmol) and anhydrous CuSO₄ (2.36 g, 10.6 mmol) in CH₂Cl₂ (10 mL) wasadded (S)-2-methylpropane-2-sulfinamide (0.641 g, 5.29 mmol). Thismixture was stirred for 25 h before being filtered through a pad ofcelite. Additional CH₂Cl₂ was used to wash the celite. The combinedorganics were concentrated in vacuo to give a residue that was purifiedby silica gel chromatography, eluting with a gradient ofhexane:EtOAc—95:5 to 0:100, to give the title compound. MS: m/z=423(M+1).

Step C. 1-Benzyl 2-methyl(2R)-2-[(3S)-3-{[(S)-tert-butylsulfinyl]amino}-3-(3,5-difluorophenyl)propyl]pyrrolidine-1,2-dicarboxylate

To a stirred solution of 1-benzyl 2-methyl(2R)-2-((3E)-3-{[(S)-tert-butylsulfinyl]imino}propyl)pyrrolidine-1,2-dicarboxylatefrom Step B (1.56 g, 3.70 mmol) in toluene (30 mL) at −78° C. was added3,5-difluorophenylmagnesium bromide (14.8 mL of a 0.5 M solution in THF,7.41 mmol) dropwise. The reaction mixture was stirred for 30 min at −78°C., 3.5 h at −10° C., and then at ambient temperature for 1.5 h. Themixture was quenched with saturated aqueous NH₄Cl (50 mL) and extractedwith EtOAc (3×30 mL). The combined organic layers were washed with brine(30 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc—95:5 to 0:100, to give the title compound. MS:m/z=537 (M+1).

Step D. Benzyl(5R,8S)-8-(3,5-difluorophenyl)-6-oxo-1,7-diazaspiro[4.5]decane-1-carboxylate

HCl (g) was bubbled through a solution of 1-benzyl 2-methyl(2R)-2-[(3S)-3-{[(S)-tert-butylsulfinyl]amino}-3-(3,5-difluorophenyl)propyl]pyrrolidine-1,2-dicarboxylatefrom Step C (1.02 g, 1.90 mmol) in MeOH (25 mL) at 0° C. for 1 min.After stirring for 1 h, the reaction mixture was concentrated to drynessin vacuo. To the crude product suspended in toluene (25 mL) was addedtriethylamine (2.12 mL, 15.2 mmol), and the reaction mixture was heatedto reflux for 66 h. The reaction mixture was concentrated in vacuo andthe crude product was purified by silica gel chromatography, elutingwith a gradient of CH₂Cl₂:MeOH:NH₄OH—100:0:0 to 95:5:1, to give thetitle compound. MS: m/z=401 (M+1).

Step E.[(5R,8S)-1-[(Benzyloxy)carbonyl]-8-(3,5-difluorophenyl)-6-oxo-1,7-diazaspiro[4.5]dec-7-yl]aceticacid

To a stirred solution of benzyl(5R,8S)-8-(3,5-difluorophenyl)-6-oxo-1,7-diazaspiro[4.5]decane-1-carboxylatefrom Step D (541 mg, 1.35 mmol) in THF (3 mL) at ambient temperature wasadded NaH (81 mg of a 60% dispersion in oil, 2.03 mmol). After 30 min,ethyl bromoacetate (0.196 mL, 1.76 mmol) was added and the mixture wasstirred for 30 min. Sodium hydroxide (8.11 mL of a 1 M solution, 8.11mmol) was added and the mixture stirred for 16 h. The reaction mixturewas poured onto 1 M HCl (20 mL) and extracted with CH₂Cl₂ (3×20 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by HPLC using areversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1 to give the title compound. MS:m/z=459 (M+1).

[(3S)-9-[(Benzyloxy)carbonyl]-3-(3,5-difluorophenyl)-1-oxo-2,9-diazaspiro[5.5]undec-2-yl]aceticacid Step A. Methyl 4-allylpiperidine-4-carboxylate

HCl (g) was bubbled through a solution of4-allyl-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid [Jiang etal. (2004) Bioorg. Med. Chem. Lett. 14, 3675-3678] (6.50 g, 24.1 mmol,)in MeOH (200 mL). The solution was heated at reflux for 16 h and thenconcentrated in vacuo to give the title compound as the hydrochloridesalt. MS: m/z=184 (M+1).

Step B. 1-Benzyl 4-methyl 4-allylpiperidine-1,4-dicarboxylate

A mixture of methyl 4-allylpiperidine-4-carboxylate from Step A (5.30 g,24.2 mmol), N-(benzyloxycarbonyloxy)succinimide (7.25 g, 29.1 mmol), andN,N-diisopropylethylamine (12.7 mL, 72.7 mmol) in CH₃CN (61 mL) wasstirred for 16 h. The solvent was removed in vacuo and the residue waspartitioned between EtOAc (100 mL) and saturated NaHCO₃ (100 mL). Theorganic layer was separated and the aqueous layer was further extractedwith EtOAc (2×100 mL). The combined organic extracts were concentratedin vacuo to give a residue that was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—100:0 to 40:60,to give the title compound. MS: m/z=318 (M+1).

Step C. 1-Benzyl 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate

To a solution of 1-benzyl 4-methyl 4-allylpiperidine-1,4-dicarboxylatefrom Step B (4.45 g, 14.0 mmol) in THF (70 mL) at 0° C. was addedborane-methyl sulfide complex (28.0 mL of a 2M solution in THF, 56.1mmol). The reaction mixture was slowly warmed to ambient temperature andstirred for 16 h, then quenched with water and concentrated in vacuo.The residue was dissolved in CH₂Cl₂ (140 mL) and added drop wise to asolution of PCC (6.65 g. 30.8 mmol) and 4 Å molecular sieves (6.65 g) inCH₂Cl₂ (50 mL) at 0° C. The reaction mixture was warmed to ambienttemperature and stirred for 16 h, then diluted with ether (200 mL) andfiltered through a pad of celite. Additional ether was used to wash thecelite. The combined organics were concentrated in vacuo to give aresidue that was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH—100:0 to 95:5, to give the title compound. MS:m/z=356 (M+Na).

[(3S)-9-[(Benzyloxy)carbonyl]-3-(3,5-difluorophenyl)-1-oxo-2,9-diazaspiro[5.5]undec-2-yl]aceticacid

Essentially, following the procedures described for Intermediate 44, butusing 1-benzyl 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate inplace of 1-benzyl 2-methyl(2R)-2-(3-oxopropyl)pyrrolidine-1,2-dicarboxylate, the title compoundwas prepared. MS: m/z=473 (M+1).

(4-Ethyl-3,6-dioxo-1-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)acetic acidStep A. Benzyl (5-chloro-3-ethyl-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate

A solution of benzyl(3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate [Parlow et al.(2003) J. Med. Chem. 46, 4050-4062] (1.05 g, 2.70 mmol), tetraethyltin(0.641 mL, 3.24 mmol), and tetrakis(triphenylphosphine)palladium (31.0mg, 0.027 mmol) in toluene (15 mL) was heated at reflux for 5.5 h. Thesolution was concentrated in vacuo and the crude product purified bysilica gel chromatography, eluting with a gradient of CH₂Cl₂:EtOAc—100:0to 90:10 to give the title compound. MS: m/z=383 (M+1).

Step B. Benzyl(4-ethyl-3,6-dioxo-1-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)acetate

A mixture of benzyl(5-chloro-3-ethyl-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate from Step A(975 mg, 2.55 mmol) in toluene (75 mL) was placed in a steel bomb. Thebomb was charged to 500 psi with ethylene, sealed, and heated at 145° C.for 66 h. The reaction mixture was concentrated in vacuo and purified bysilica gel chromatography, eluting with a gradient of CH₂Cl₂:EtOAc—100:0to 0:100, to give the title compound. MS: m/z=393 (M+1).

Step C.(4-Ethyl-3,6-dioxo-1-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)acetic acid

To a solution of benzyl(4-ethyl-3,6-dioxo-1-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)acetate fromStep B (30 mg, 0.076 mmol) in EtOH (1 mL) at ambient temperature wasadded NaOH (0.229 mL of a 1M solution, 0.229 mmol). The reaction mixturewas stirred at ambient temperature for 2 h, and at 50° C. for 2 h. Thesolvent was removed in vacuo and the crude product dissolved in DMSO andpurified by HPLC using a reversed phase C18 column and eluting with agradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1 to give the titlecompound as the TFA salt. MS: m/z=303 (M+1).

(4-Ethyl-3-oxo-1-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)acetic acid StepA. Benzyl(4-ethyl-3-oxo-1-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)acetate

To a solution of benzyl(4-ethyl-3,6-dioxo-1-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)acetate (200mg, 0.510 mmol, described in Intermediate 46) in THF (5 mL) at ambienttemperature was added borane-methyl sulfide complex (0.535 mL of a 2Msolution in THF, 1.07 mmol). The reaction mixture was heated at 65° C.for 2 h, then cooled and quenched with 1M HCl (5 mL). The reactionmixture was poured onto saturated NaHCO₃ (10 mL) and extracted withEtOAc (3×20 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was dissolved inDMSO and purified by HPLC using a reversed phase C18 column and elutingwith a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1 to give thetitle compound as the TFA salt. MS: m/z=379 (M+1).

Step B. (4-Ethyl-3-oxo-1-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)aceticacid

A mixture of benzyl(4-ethyl-3-oxo-1-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)acetate fromStep A (127 mg, 0.336 mmol) and 10% Pd/C (20 mg) in MeOH (5 mL) wasstirred under a balloon of hydrogen. The reaction mixture was filteredand concentrated in vacuo to give the title compound. MS: m/z=289 (M+1).

The intermediates appearing in the following tables were prepared byanalogy to the above intermediates, as described or prepared as a resultof similar transformations with modifications known to those skilled inthe art. The requisite starting materials were described herein (videsupra), commercially available, known in the literature, or readilysynthesized by one skilled in the art. Straightforward protecting groupstrategies were applied in some routes. In some cases, relevantexperimental procedures are indicated in the tables.

TABLE 1

Relevant LCMS experimental Intermediate R⁶ R⁷ R¹⁰ R¹¹ * (M + 1)procedures 48 Me Me H 3,4-difluorophenyl ± 298 49 Me Me H3,5-difluorophenyl S 298 Int. 1  50 Me Me H 3-chloro-4-fluorophenyl S314 Int. 14 51 Me Me H 5-fluoro-2-methylphenyl S 294 Int. 14 52 Me Me H4-fluoro-2-methylphenyl S 294 Int. 14 53 Me Me H 4-fluoro-3-methylphenylS 294 Int. 14 54 Me Me H 5-fluoro-2-methoxyphenyl S 310 Int. 14 55 Me MeH 3-fluorophenyl S 280 Int. 14 56 Me Me H 4-chloro-3-fluorophenyl S 314Int. 14 57 Me Me H 3-fluoro-2-methylphenyl S 294 Int. 14 58 Me Me H2-methoxyphenyl S 292 Int. 14 59 Me Me H 4-methoxyphenyl S 292 Int. 1460 Me Me H 3-methoxyphenyl S 292 Int. 14 61 Me Me Me 3,5-difluorophenylS 312 Ex. 4  62 Me Me H 3,5-dichlorophenyl S 330 Int. 14 63 Me Me H3-thienyl S 268 Int. 14 64 Me Me H 2-thienyl S 268 Int. 14 65 Me Me H3-chloro-2-thienyl S 302 Int. 14 66 Me Me H 1,3-benzodioxol-5-yl S 306Int. 14 67 Me Me H 3-fluoro-4-methoxyphenyl S 310 Int. 14 68 Me Me H3-chloro-5-fluorophenyl S 314 Int. 14 69 Me Me H phenyl S 262 Int. 14 70Me Me H 2-trifluoromethylphenyl S 330 Int. 14 71 Me Me H 4-fluorophenylS 280 Int. 14 72 Me Me H 2-(methylthio)phenyl S 308 Int. 14 73 Me Me Hcyclohexyl S 268 Int. 14 74 Me Me H cyclopropyl S 226 Int. 14 75 Me Me H3-chlorophenyl S 296 Int. 14 76 Me Me H 3,4-dichlorophenyl S 330 Int. 1477 Me Me H 3-methylphenyl S 276 Int. 14 78 Me Me H 4-methylphenyl S 276Int. 14 79 Me Me H 4-(methylthio)phenyl S 308 Int. 14 80 Me Me H4-chloro-2-methylphenyl S 310 Int. 14 81 Me Me H benzyl S 276 Int. 14 82Me Me H 4-chlorophenyl S 296 Int. 14 83 Me Me H isopropyl S 228 Int. 1484 Me Me H 2-methylphenyl S 276 Int. 14 85 Me Me H3-chloro-2,4-difluorophenyl 332 Int. 18

TABLE 2

Relevant Inter- LCMS experimental mediate n R¹⁰ R¹¹ * (M + 1) procedures86 3 H 3,5-difluorophenyl S 324 Int. 26 87 4 H 3,5-difluorophenyl S 338Int. 26 88 1 H phenyl ± 260 Int. 26

TABLE 3

Relevant LCMS experimental Intermediate R⁶ R⁷ A¹ R¹⁰ R¹¹ * (M + 1)procedures 89 Me Me O H phenyl R 264 Int. 10 90 Me Me O H3,5-difluorophenyl S 300 Int. 10 91 H Et O H phenyl R 264 Int. 12 92 MeMe CF₂ H 3,5-difluorophenyl S 334 Int. 22 93 Me Me 1,3-dioxolan-2-yl H3,5-difluorophenyl S 356 Int. 22

TABLE 4

Relevant LCMS experimental Intermediate R⁶ R⁷ R¹¹ * (M + 1) procedures94 Me Me 3,5-difluorophenyl R 312 Int. 22 95 Et Et 3,5-difluorophenyl S340 Int. 22 96 Et Et 3,5-difluorophenyl R 340 Int. 22

TABLE 5

Relevant Inter- LCMS experimental mediate R⁶ R⁷ R * R¹¹ % (M + 1)procedures 97 Me Me H R 3,5-difluoro- R 314 Int. 21 phenyl 98 Me Me H R3,5-difluoro- S 314 Int. 21 phenyl 99 Me Me H S 3,5-difluoro- R 314 Int.21 phenyl 100 Me Me Me S 3,5-difluoro- S 328 Int. 21 phenyl 101 Et Et HS 3,5-difluoro- S 342 Int. 21 phenyl 102 Et Et H R 3,5-difluoro- R 342Int. 21 phenyl 103 Me Me Me R 3,5-difluoro- R 328 Int. 21 phenyl

TABLE 6

Relevant LCMS experimental Intermediate R⁶ R⁷ R¹ R¹¹ * (M + 1)procedures 104 Me Me tert-butoxycarbonyl phenyl ± 307 (M − Int. 13 C₄H₇)105 Me Me tert-butoxycarbonyl phenyl S 307 (M − Int. 13 C₄H₇) 106 Me Metert-butoxycarbonyl phenyl R 307 (M − Int. 13 C₄H₇) 107 Me Metert-butoxycarbonyl 3,5-difluorophenyl S 343 (M − Int. 13 C₄H₇) 108 Me HMe phenyl ± 263 Int. 19 109 H Bn Me phenyl S 339 Int. 19 110 H Bn Mephenyl R 339 Int. 19 111 Et Et Me phenyl ± 305 Int. 19 112 Et Et Hphenyl ± 291 Int. 25 113 Et Et H 3,5-difluorophenyl S 327 Int. 29 114 HPh Me phenyl S 325 Int. 19 115 H Ph Me phenyl R 325 Int. 19 116 H i-PrMe phenyl S 291 Int. 19 117 H i-Pr Me phenyl R 291 Int. 19 118 H i-Bu Mephenyl S 305 Int. 19 119 H i-Bu Me phenyl R 305 Int. 19 120 i-Bu H Mephenyl S 305 Int. 19 121 i-Bu H Me phenyl R 305 Int. 19 122 CH₂CF₃ Htert-butoxycarbonyl 3,5-difluorophenyl R 397 (M − Int. 25 C₄H₇) 123CH₂CF₃ H H 3,5-difluorophenyl S 353 Int. 25 124 H CH₂CF₃ H3,5-difluorophenyl R 353 Int. 25 125 Me Me PhCH₂ 3,5-difluorophenyl R389 Int. 13 126 Me Me CF₃CH₂ 3,5-difluorophenyl R 381 Int. 13

TABLE 7

Relevant experimental Intermediate R¹ n R¹⁰ R¹¹ * LCMS (M + 1)procedures 127 H 3 H phenyl S 289 Int. 28 128 Me 1 H phenyl ± 275 Int.19 129 Me 2 H phenyl ± 289 Int. 19 130 H 3 H 3,5-difluorophenyl S 325Int. 25 131 H 4 H 3,5-difluorophenyl R 339 Int. 29 132 H 4 H3,5-difluorophenyl S 339 Int. 29 133 tert-butoxycarbonyl 4 Me3,5-difluorophenyl S 397 (M − Int. 33 C₄H₇) 134 tert-butoxycarbonyl 5 Me3,5-difluorophenyl R 411 (M − Int. 33 C₄H₇) 135 tert-butoxycarbonyl 5 Me3,5-difluorophenyl S 411 (M − Int. 33 C₄H₇) 136 tert-butoxycarbonyl 3 Me3,5-difluorophenyl R 383 (M − Int. 33 C₄H₇) 137 tert-butoxycarbonyl 3 Me3,5-difluorophenyl S 383 (M − Int. 33 C₄H₇)

TABLE 8

Relevant LCMS experimental Intermediate R⁶ # R¹¹ * (M + 1) procedures138 H S phenyl R 275 Int. 28 139 H S phenyl S 275 Int. 28 140 H R phenylR 275 Int. 28 141 H R phenyl S 275 Int. 28 142 Me S phenyl ± 289 Int. 28143 Me S 3,5-difluorophenyl ± 325 Int. 28

TABLE 9

Relevant LCMS experimental Intermediate R⁶ R⁷ R¹ R² # R¹¹ * (M + 1)procedures 144 Me Me H Me R phenyl R 277 Int. 25 145 Me Me H Me S phenylS 277 Int. 25 146 Me Me H Me R 3,5-difluorophenyl R 313 Int. 25 147 MeMe H Me S 3,5-difluorophenyl S 313 Int. 25

TABLE 10

Relevant Inter- LCMS experimental mediate R¹ X R¹⁰ R¹¹ * (M + 1)procedures 148 H O H 3,5-difluoro- R 341 Int. 25 phenyl 149 H O H3,5-difluoro- S 341 Int. 25 phenyl

TABLE 11

Relevant experimental Intermediate R¹ n X * LCMS (M + 1) procedures 150tert-butoxy- 3 F S 451 Int. 34 carbonyl 151 tert-butoxy- 3 H ± 437 (M +Na) Int. 34 carbonyl

EXAMPLE 1

N-[(4S)-3-Methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]-2-((6±)-2-oxo-6-phenylpiperidin-1-yl)acetamideStep A. (±)-(2-Oxo-6-phenylpiperidin-1-yl)acetic acid

To a stirred solution of (±)-6-phenylpiperidin-2-one (155 mg, 0.885mmol) in THF (10 mL), cooled to 0° C., was added NaH (30.0 mg, 1.24mmol). The ice bath was removed and the reaction was allowed to warm toambient temperature. After 1 h at ambient temperature, the reaction wascooled to 0° C. prior to the introduction of methyl bromoacetate (149mg, 0.973 mmol). After 40 minutes, the ice bath was removed and thereaction was stirred under nitrogen for 12 h. Additional quantities ofNaH and methyl bromoacetate were then added in parts to nearly consumethe lactam, as judged by LCMS analysis. After sufficient lactam wasconsumed, 1 M aqueous sodium hydroxide was added (1 mL, 1 mmol). After amajority of the methyl ester was saponified (˜3 h), the reaction wasquenched with 1 M hydrochloric acid (5 mL), and EtOAc (50 mL). Theorganics were washed with saturated brine (twice), dried over sodiumsulfate, filtered and concentrated in vacuo, to yield a residue whichwas used without further purification. MS: m/z=234 (M+1).

Step B.N-[(4S)-3-Methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]-2-((6±)-2-oxo-6-phenylpiperidin-1-yl)acetamide

To a solution of (±)-(2-oxo-6-phenylpiperidin-1-yl)acetic acid from StepA (100. mg, 0.429 mmol), HOAt (29.0 mg, 0.214 mmol) and(4S)-5′-amino-3-methyl-1′,3′-dihydro-2H,5H-spiro[imidazolidine-4,2′-indene]-2,5-dione(109 mg, 0.472 mmol, prepared according to Bell, I. M., et al., PCT Int.Appl., WO 2004082605 A2) in DMF (5.0 mL) was added EDCI (115 mg, 0.600mmol). This solution was stirred at ambient temperature for 15 h. Thereaction was then quenched by the addition of 1 M HCl (10 mL) and EtOAc(50 mL). The organics were further washed with an additional aliquot of1M HCl (10 mL), then saturated brine (20 mL×2), followed by drying oversodium sulfate. The organics were then filtered, concentrated in vacuo,and applied to a silica gel column for purification, eluting with agradient of CH₂Cl₂:MeOH—99.5:0.5 to 95:5. Clean product-containingfractions were pooled and concentrated in vacuo to give the titlecompound. MS: m/z=447 (M+1). FIRMS: m/z=447.2013; calculatedm/z=447.2027 for C₂₅H₂₇N₄O₄.

EXAMPLE 2

2-[(5R)-5-(3,5-Difluorophenyl)-2,2-dimethyl-3-oxo-4-thiomorpholinyl]-N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]acetamide

Starting from(5R)-5-(3,5-difluorophenyl)-2,2-dimethylthiomorpholin-3-one(Intermediate 2), the compound in Example 2 was prepared followinganalogous procedures for the preparation of Example 1, to provide thetitle compound. MS: m/z=551 (M+Na). HRMS: m/z=529.1734; calculatedm/z=529.1716 for C₂₆H₂₆F₂N₄O₄S.

EXAMPLE 3

2-[(5R)-5-(3,5-Difluorophenyl)-2,2-dimethyl-1-oxido-3-oxo-4-thiomorpholinyl]-N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]acetamideStep A. (5R)-5-(3,5-Difluorophenyl)-2,2-dimethylthiomorpholin-3-one

To a solution of2-[(5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxo-4-thiomorpholinyl]-N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]acetamide(Example 2) in 1.5 mL chloroform at 0° C., was added3-chloroperoxybenzoic acid (21 mg with a purity of 77%, 0.121 mmol). AnLCMS of the reaction mixture after two hours showed that all startingmaterial was consumed. Calcium hydroxide (14 mg, 0.185 mmol) was addedto the reaction and stirred for forty minutes. The mixture was thenvacuum filtered through filter paper and the solid was washed withchloroform (3×10 mL). The filtrate was concentrated in vacuo to give aresidue that was purified by silica gel chromatography, eluting with agradient of MeOH:CH₂Cl₂—1:99 to 5:95, to give the title compound. MS:m/z=545 (M+H). HRMS: m/z=545.1653; calculated m/z=545.1665 forC₂₆H₂₆F₂N₄O₅S.

EXAMPLE 4

2-[(2S)-2-(3,5-Difluorophenyl)-2,5,5-trimethyl-6-oxo-1-piperidinyl]-N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]acetamideStep A. Methyl(5E)-5-[tert-butylsulfinyl)imino]-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate

To a solution of methyl5-(3,5-difluorophenyl)-2,2-dimethyl-5-oxopentanoate from Intermediate 1,Step D (500 mg of 85% purity, 1.85 mmol) and(S)-2-methylpropane-2-sulfinamide (336 mg, 2.78 mmol) in THF (9.5 mL),was added titanium tetraethoxide (904 mg, 3.70 mmol). The reactionvessel was quickly sealed and placed into a 60° C. bath for 2 hours.After cooling to ambient temperature the reaction mixture was thendiluted with saturated brine (9.5 mL) while experiencing rapid stirring.The resultant slurry was filtered through celite, washing with EtOAc, asneeded. The combined organics were then washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo to give an oil. Thisoil was purified by silica gel chromatography, eluting with a gradientof MeOH:CH₂Cl₂—0.5:99.5 to 3:97, to give the title compound. MS: m/z=374(M+1).

Step B. Methyl(5S)-5-[(tert-butylsulfinyl)amino]-5-(3,5-difluorophenyl)-2,2-dimethylhexanoate

To a solution of methyl(5E)-5-[(tert-butylsulfinyl)imino]-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate(342 mg, 0.920 mmol) in CH₂Cl₂ (6 mL) at 0° C., was added dropwise overfive minutes methyl magnesium bromide as a 3M solution in diethyl ether(0.61 mL, 1.83 mmol). After 15 minutes the reaction was determined to becomplete by LCMS analysis. The reaction was quenched by the dropwiseaddition of 1M HCl (5 mL), followed by 5 mL of water. The aqueous layerwas extracted once with CH₂Cl₂ (10 mL) and the organics were combinedand washed once with brine (15 mL). The organics were dried over sodiumsulfate, filtered and concentrated in vacuo to give a residue that waspurified by silica gel chromatography, eluting with a gradient ofEtOAc:Hexanes—10:90 to 55:45, to give the title compound. MS: m/z=390(M+1).

Step C. (6S)-6-(3,5-Difluorophenyl)-3,3,6-trimethylpiperidin-2-one

To a solution of methyl(5S)-5-[(tert-butylsulfinyl)amino]-5-(3,5-difluorophenyl)-2,2-dimethylhexanoate(1.14 g, 2.93 mmol) in MeOH (60 mL), cooled to 0° C., was addedanhydrous HCl gas for 1 minute. The reaction was sealed and allowed tosit at 0° C. for fifteen minutes at which point the reaction wascomplete by LCMS analysis. Nitrogen was bubbled through the reaction fortwenty minutes. The reaction was concentrated in vacuo. Additional MeOH(50 mL) was added and it was again concentrated in vacuo. This wasrepeated with another addition of MeOH and triethylamine (1.18 g, 11.7mmol). To the resulting residue was added toluene (50 mL) andtriethylamine (1.18 g, 11.7 mmol). A reflux condenser was attached andthe mixture stirred at 110° C. After five days of stirring at reflux,the reaction was judged to be complete by LCMS. The mixture was cooledto ambient temperature and concentrated in vacuo. The residue wasdiluted with diethyl ether (75 mL) and washed individually with 30 mL ofeach of the following aqueous solutions: 1M HCl (twice), water,saturated brine. The organic layer was then dried over sodium sulfate,filtered, and concentrated in vacuo to give a residue that was purifiedby silica gel chromatography, eluting with a gradient ofMeOH:CH₂Cl₂—1:99 to 5.5:94.5, to give the title compound. MS: m/z=254(M+1).

Step D. Methyl[(2S)-2-(3,5-difluorophenyl)-2,5,5-trimethyl-6-oxopiperidin-1-yl]acetate

To a solution of(6S)-6-(3,5-difluorophenyl)-3,3,6-trimethylpiperidin-2-one (540. mg,2.13 mmol) in THF (20 mL), chilled to 0° C. was added potassium hydride(approximately 86 mg, 2.13 mmol, as a 30% suspension in oil) under aconstant stream of nitrogen. The reaction was allowed to stir for 30minutes at which time methyl bromoacetate (391 mg, 2.56 mmol) was addedat 0° C. An LCMS after one hour indicated that the reaction wasincomplete, thus more potassium hydride was added (approximately 43 mg,1.06 mmol, as a 30% suspension in oil) at 0° C. The reaction was sealedwell and was stirred for an additional 16 hours, during which time thebath temperature warmed to ambient temperature. The reaction was judgedto be 46% complete by LCMS analysis. The reaction was chilled to 0° C.and saturated aqueous ammonium chloride (5 mL) was added to quench thepotassium hydride. To the reaction was added 1M aqueous HCl (5 mL) andthe reaction was diluted with ethyl acetate. The organic layer waswashed once with brine and then dried over sodium sulfate, filtered, andconcentrated in vacuo to give a residue that was purified by silica gelchromatography, eluting with a gradient of EtOAc:Hexanes—10:90 to 75:25,to give the title compound. MS: m/z=326 (M+1).

Step E. Potassium[(2S)-2-(3,5-difluorophenyl)-2,5,5-trimethyl-6-oxopiperidin-1-yl]acetate

To a solution of methyl[(2S)-2-(3,5-difluorophenyl)-2,5,5-trimethyl-6-oxopiperidin-1-yl]acetatefrom Step D (298 mg, 0.916 mmol) in THF (9 mL) at ambient temperaturewas added potassium trimethylsilanolate (147 mg, 1.14 mmol). Thereaction was stirred for 24 hours and found to be incomplete by LCMSanalysis. Additional quantities of potassium trimethylsilanolate wereadded as needed. The reaction was concentrated in vacuo to give aresidue that required no further purification. MS: m/z=312 (M+1 forparent acid).

Step F.2-[(2S)-2-(3,5-Difluorophenyl)-2,5,5-trimethyl-6-oxo-1-piperidinyl]-N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]acetamide

Starting from potassium[(2S)-2-(3,5-difluorophenyl)-2,5,5-trimethyl-6-oxopiperidin-1-yl]acetate(182 mg, 0.522 mmol), Example 4 was prepared following the analogousprocedure for the preparation of Example 1, Step B, to provide the titlecompound. MS: m/z=525 (M+1). HRMS: m/z=525.2326; calculated m/z=525.2308for C₂₈H₃₀F₂N₄O₄.

EXAMPLE 5

N-(3-Methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl)-2-(6-oxo-2-phenyltetrahydropyridazin-1(2H)-yl)acetamide

Starting from 1-phenyltetrahydropyridazin-3(2H)-one (prepared accordingto Hwang, K.-J.; Park K.-H., Heterocycles, 1993, 36, 219-222), thecompound in Example 5 was prepared following analogous procedures forthe preparation of Example 1, to provide the title compound. MS: m/z=448(M+1). HRMS: m/z=448.1965; calculated m/z=448.1980 for C₂₄H₂₆N₅O₄.

EXAMPLE 6

2-[(4S,6S)-6-(3,5-Difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

A mixture of[(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]aceticacid (130 mg, 0.415 mmol, described in Intermediate 21),(R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (140 mg, 0.557mmol, described in Intermediate 9), HOBT (82 mg, 0.535 mmol), and EDC(95 mg, 0.498 mmol) in DMF (2 mL) was stirred at ambient temperature for6 h. The reaction mixture was partitioned between H₂O (50 mL), saturatedaqueous NaHCO₃ (30 mL) and EtOAc (100 mL). The organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofCH₂Cl₂:CH₃OH—100:0 to 90:10, to give the title compound. MS: m/z=547(M+1). HRMS: m/z=547.2169; calculated m/z=547.2151 for C₃₀H₂₉F₂N₄O₄.

EXAMPLE 7

2-[(6S)-6-(3,5-Difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′-tetrahydrospiro[indene-2,3′-pyrrolo [2,3-b]pyridin]-5-yl]acetamide

A mixture of[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]aceticacid (156 mg, 0.501 mmol, described in Intermediate 22),(R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(145 mg, 0.577 mmol, described in Intermediate 9), HOBT (95 mg, 0.620mmol), and EDC (123 mg, 0.642 mmol) in DMF (2 mL) was stirred at ambienttemperature for 16 h. The reaction mixture was partitioned between H₂O(60 mL) and EtOAc (100 mL). The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of CH₂Cl₂:CH₃OH—100:0to 90:10, to give the title compound. MS: m/z=545 (M+1). HRMS:m/z=545.2025; calculated m/z=545.1995 for C₃₀H₂₇F₂N₄O₄.

EXAMPLE 8

2-[(4S,6S)-4-Amino-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

A mixture of2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide(380 mg, 0.698 mmol, described in Example 7) and NH₄OAc (571 mg, 7.41mmol) in CH₃OH (2 mL) was stirred at ambient temperature for 20 min.NaCNBH₃ (498 mg, 7.92 mmol) was added and stirring was continued atambient temperature for 12 h. The reaction mixture was diluted with H₂O(40 mL) and aqueous NaHCO₃ (70 mL) and extracted with EtOAc (2×100 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:CH₃OH—100:0 to 80:20,to give2-[(4R,6S)-4-amino-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide,which eluted first, and2-[(4S,6S)-4-amino-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide,which eluted second, the title compound. MS: m/z=546 (M+1). HRMS:m/z=546.2287; calculated m/z=546.2311 for C₃₀H₃₀F₂N₅O₃.

EXAMPLE 9

2-[(6S)-6-(3,5-Difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-methyl-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamideStep A.2-[(6S)-6-(3,5-Difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-((2R)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

A mixture of[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]aceticacid (21 mg, 0.07 mmol, described in Intermediate 49),(R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(26 mg, 0.07 mmol, described in Intermediate 9, step B), HOBT (15 mg,0.10 mmol), and EDC (19 mg, 0.10 mmol) in DMF (0.5 mL) was stirred atambient temperature for 18 h. The reaction mixture was partitionedbetween saturated aqueous NaHCO₃ (10 mL) and EtOAc (20 mL). The organiclayer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound. MS: m/z=661 (M+1).

Step B.2-[(6S)-6-(3,5-Difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-methyl-N-((2R)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

To a stirred solution of2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-((2R)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamidefrom Step A (47 mg, 0.07 mmol) in DMF (1 mL) at 0° C. was added NaH (11mg of a 60% dispersion in oil, 0.28 mmol). After 15 min, iodomethane (30mg, 0.21 mmol) was added and the mixture was allowed to warm to ambienttemperature and was stirred for 1 h. The reaction mixture was quenchedwith H₂O (5 mL) and the precipitate was isolated by filtration, washedwith H₂O, and dried in vacuo to provide the title compound. MS: m/z=675(M+1).

Step C.2-[(6S)-6-(3,5-Difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-methyl-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

To a solution of2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-methyl-N4(2R)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamidefrom Step B (38 mg, 0.057 mmol) in CH₂Cl₂ (2 mL) was added TFA (1 mL)and the resulting mixture was stirred at ambient temperature for 1 hthen concentrated to dryness in vacuo. The residue was dissolved in MeOH(1 mL) and the solution was adjusted to pH 10 by addition of 1 N aqueousNaOH and ethylenediamine (5.7 mg, 0.095 mmol). After 30 min, the mixturewas partitioned between H₂O (30 mL) and EtOAc (40 mL). The organic layerwas washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of CH₂Cl₂:CH₃OH—100:0 to 95:5, to give the titlecompound. MS: m/z=545 (M+1). HRMS: m/z=545.2388; calculated m/z=545.2359for C₃₁H₃₁F₂N₄O₃.

EXAMPLE 10

2-[(6R)-6-(3,5-Difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

A mixture of[(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetic acidhydrochloride (43 mg, 0.119 mmol, described in Intermediate 29),(R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(30 mg, 0.119 mmol, described in Intermediate 9), HOBT (27 mg, 0.179mmol), and EDC (34 mg, 0.179 mmol) in DMF (0.5 mL) was stirred atambient temperature for 18 h. The reaction mixture was purified directlyby HPLC using a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The pure, product-containingfractions were combined, basified with saturated aqueous NaHCO₃, andextracted with EtOAc. The organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo to give the title compound. MS:m/z=560 (M+1). HRMS: m/z=560.2469; calculated m/z=560.2468 forC₃₁H₃₂F₂N₅O₃.

EXAMPLE 11

2-[(6S)-(3,5-Difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-7′-oxido-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

A mixture of2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide(20.0 mg, 0.038 mmol, described in Example 49) and Oxone® (70.0 mg,0.113 mmol) in MeOH (0.5 mL) and water (0.5 mL) was stirred at ambienttemperature for 3 h. The reaction mixture was purified directly by HPLCusing a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Lyophilization provided thetitle compound. MS: m/z=547 (M+1). HRMS: m/z=547.2155; calculatedm/z=547.2152 for C₃₀H₂₉F₂N₄O₄.

EXAMPLE 12

2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamidehydrochloride

A mixture of lithium[(8R)-6-(tert-butoxycarbonyl)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate(30 mg, 0.070 mmol, described in Intermediate 32),(R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(20 mg, 0.079 mmol, described in Intermediate 9), HOBT (14 mg, 0.092mmol), and EDC (18 mg, 0.092 mmol) in DMF (0.5 mL) was stirred atambient temperature for 18 h. The reaction mixture was diluted withEtOAc (5 mL) and washed successively with 10% citric acid (2 mL), H₂O (2mL), saturated aqueous NaHCO₃ (2 mL), and brine (2 mL). The organiclayer was dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography, eluting withCH₂Cl₂:EtOAc—100:0 to 0:100, to give the Boc-protected product. TheBoc-protected product was dissolved in EtOAc (3 mL), the solution wascooled to 0° C., and HCl (g) was bubbled in for 1 min. The mixture wasaged at 0° C. for 15 min and the title compound was isolated byfiltration. MS: m/z=558 (M+1). HRMS: m/z=558.2300; calculatedm/z=558.2311 for C₃₁H₃₀F₂N₅O₃.

EXAMPLE 13

2-[(6R)-6-(3,5-Difluorophenyl)-3,3-dimethyl-2-oxopiperazin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamidehydrochloride

To a mixture of lithium[(6R)-4-(tert-butoxycarbonyl)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperazin-1-yl]acetate(1.12 g, 2.77 mmol, described in Intermediate 13),(R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(835 mg, 3.32 mmol, described in Intermediate 9), and HATU (1.26 g, 3.32mmol) in DMF (12 mL) was added N-methylmorpholine (0.61 mL, 5.54 mmol)and the resulting mixture was stirred at ambient temperature for 90 min.The reaction mixture was diluted with EtOAc (500 mL) and washedsuccessively with 10% citric acid (100 mL), H₂O (100 mL), saturatedaqueous NaHCO₃ (100 mL), and brine (100 mL). The organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography, eluting with CH₂Cl₂:MeOH—100:0 to90:10, to give the Boc-protected product. The Boc-protected product wasdissolved in EtOAc (75 mL), the solution was cooled to 0° C., and HCl(g) was bubbled in for 2 min. After 15 min, additional HCl (g) wasbubbled in for 1 min. The mixture was aged at 0° C. for 30 min andconcentrated in vacuo to provide the title compound. MS: m/z=532 (M+1).HRMS: m/z=532.2172; calculated m/z=532.2155 for C₂₉H₂₈F₂N₅O₃.

EXAMPLE 14

2-[2-(3,4-Difluorophenyl)-5,5-dimethylpiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

Essentially following the procedures described for Example 6, but using[2-(3,4-difluorophenyl)-5,5-dimethylpiperidin-1-yl]acetic acid(described in Intermediate 23) in place of[(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]aceticacid, the title compound was obtained. MS: m/z=517 (M+1). HRMS:m/z=517.2432; calculated m/z=517.2410 for C₃₀H₃₁F₂N₄O₂.

EXAMPLE 15

2-[(9S)-11-Oxo-9-phenyl-6,10-diazaspiro[4.6]undec-10-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamideStep A. Methyl1-({(3S)-3-[(2-oxo-2-{[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]amino}ethyl)amino]-3-phenylpropyl}amino)cyclopentanecarboxylate

To a cooled (0° C.) solution of(2R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(0.100 g, 0.398 mmol, Intermediate 9) and triethylamine (100. μL, 0.716mmol) in THF (8 mL) was added bromoacetyl bromide (46.0 μL, 0.523 mmol).After allowing the reaction to warm to ambient temperature,triethylamine (0.230 mL, 1.67 mmol) and methyl1-{[(3S)-3-amino-3-phenylpropyl]amino}cyclopentanecarboxylatebis-hydrochloride (0.139 g, 0.398 mmol, Intermediate 38) were added,prior to heating the reaction to 50° C. for 17 h. After cooling toambient temperature, the reaction mixture was diluted with chloroformand saturated aqueous sodium bicarbonate. The aqueous layer wasextracted twice with additional chloroform. The combined organics weredried over sodium sulfate, filtered and concentrated in vacuo to give anoil. This oil was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH:NH₄OH—99:1:0.1 to 92:8:0.8, to give the titlecompound. MS: m/z=568 (M+1).

Step B. Potassium1-({(3S)-3-[(2-oxo-2-{[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]amino}ethyl)amino]-3-phenylpropyl}amino)cyclo-pentanecarboxylate

To a stirred solution of methyl1-({(3S)-3-[(2-oxo-2-{[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]amino}ethyl)amino]-3-phenylpropyl}amino)cyclopentanecarboxylatefrom Step A (0.141 g, 0.249 mmol) in dry THF (5 mL) was added KOTMS(64.0 mg, 0.498 mmol) and the reaction mixture was heated to 40° C., atwhich point the desired product began to precipitate. Two additionalquantities of KOTMS (˜60 mg×2) were added over the next 2 h resulting ina complete consumption of starting material. The mixture was thenallowed to cool to ambient temperature. The THF, which contained onlytraces of product, was then decanted away from the precipitated product.This solid was then washed with two additional quantities of anhydrousTHF (5 mL×2), to provide the title compound. MS: m/z=554 (M+1).

Step C.2-[(9S)-11-Oxo-9-phenyl-6,10-diazaspiro[4.6]undec-10-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

To a stirred solution of potassium1-({(3S)-3-[(2-oxo-2-{[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]amino}ethyl)amino]-3-phenylpropyl}amino)cyclopentanecarboxylatefrom Step B (0.147 g, 0.249 mmol) in DMF (8.3 mL) was added EDCI (0.0720g, 0.374 mmol) and HOAt (0.0340 g, 0.249 mmol). The reaction mixture wasthen heated to 40° C. After 1 h, additional EDCI (0.0350 mg) was addedand the reaction temperature was increased to 50° C., for 15 h. Thereaction was allowed to cool to ambient temperature before being dilutedwith 5% aqueous sodium bicarbonate (100 mL) and chloroform (100 mL). Theorganics were washed successively with water (100 mL) and saturatedbrine (100 mL). The combined organics were dried over sodium sulfate,filtered and concentrated in vacuo to give an oil. This oil was purifiedby silica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH—99:1 to 91:9, to give the title compound. MS: m/z=536 (M+1).HRMS: m/z=536.2694; calculated m/z=536.2656 for C₃₂H₃₄N₅O₃.

EXAMPLE 16

N-[(4S)-3-Methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]-2-[(9S)-11-oxo-9-phenyl-6,10-diazaspiro[4.6]undec-10-yl]acetamideStep A. (9S)-9-Phenyl-6,10-diazaspiro[4.6]undecan-11-one

Potassium trimethylsilanoate (1.21 g, 9.45 mmol) was added to a stirredsuspension of methyl1-{[(3S)-3-amino-3-phenylpropyl]amino}cyclopentanecarboxylatebis-hydrochloride (1.00 g, 2.86 mmol, Intermediate 38) in THF (5.0 mL)at ambient temperature. After 4 h, the reaction mixture was adjusted topH=8 with aqueous 1 M HCl. To this mixture was added HOAt (0.195 g, L43mmol), and EDCI (0.549 g, 2.87 mmol). After 1 h, the reaction wasconcentrated in vacuo. The residue was partitioned between CH₂Cl₂ andwater. The aqueous phase was extracted several times with CH₂Cl₂. Thecombined organic extracts were washed with saturated brine, then driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedby silica gel chromatography, eluting with CH₂Cl₂:MeOH:NH₄OH—89.9:10:0.1to give the title compound. MS: m/z=245 (M+1).

Step B. Benzyl[(9S)-11-oxo-9-phenyl-6,10-diazaspiro[4.6]undec-10-yl]acetate

To a suspension of sodium hydride (0.147 g, 6.14 mmol) in THF (10 mL)was added (9S)-9-phenyl-6,10-diazaspiro[4.6]undecan-11-one (0.300 g,1.23 mmol) at ambient temperature. The reaction was warmed to 60° C. for2 h, then cooled to ambient temperature. Benzyl bromoacetate (0.309 g,1.35 mmol) was added dropwise to the reaction. After 1 h, the mixturewas quenched with a saturated aqueous ammonium chloride solution. Themixture was concentrated in vacuo then partitioned between H₂O andCH₂Cl₂. The aqueous phase was then extracted several times with CH₂Cl₂.The combined organic extracts were washed with saturated brine, thendried over MgSO₄, filtered and concentrated in vacuo The residue waspurified by silica gel chromatography, eluting with a gradient ofEtOAc:hexane—0:100 to 100:0, to yield the title compound. MS: m/z=393(M+1).

Step C. [(9S)-11-Oxo-9-phenyl-6,10-diazaspiro[4.6]undec-10-yl]aceticacid

A solution of benzyl[(9S)-11-oxo-9-phenyl-6,10-diazaspiro[4.6]undec-10-yl]acetate from StepB (0.190 g, 0.484 mmol) in methanol (10 mL) was passed through anH-Cube™ continuous flow hydrogenation reactor at 50 Bar of H₂ using aPd/C catalyst at ambient temperature. The solution was concentrated invacuo to yield the title compound. MS: m/z=303 (M+1).

Step D.N-[(4S)-3-Methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]-2-[(9S)-11-oxo-9-phenyl-6,10-diazaspiro[4.6]undec-10-yl]acetamide

To a solution of[(9S)-11-oxo-9-phenyl-6,10-diazaspiro[4.6]undec-10-yl]acetic acid fromStep C (0.0516 g, 0.171 mmol),(4S)-5′-amino-3-methyl-1′,3′-dihydro-2H,5H-spiro[imidazolidine-4,2′-indene]-2,5-dione(0.0370 g, 0.162 mmol, prepared according to Bell, I. M., et al., PCTInt. Appl., WO 2004082605 A2), and HOAt (0.0120 g, 0.085 mmol) in THF (5mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.0460 g, 0.239 mmol), at ambient temperature. Uponcompletion of the reaction, as judged by LCMS, the reaction mixture wasconcentrated in vacuo. The residue was purified by silica gelchromatography, eluting with a gradient of EtOAc:hexane—5:95 to 100:0,followed by HPLC using a reversed phase C18 column and eluting with agradient of H₂O:CH₃CN:CF₃CO₂H—95:5:0.1 to 65:35:0.1. The pure,product-containing fractions were concentrated in vacuo, neutralizedwith aqueous NaHCO₃, and extracted several times with CH₂Cl₂. Thecombined organic extracts were washed with saturated brine, dried overMgSO₄, filtered and concentrated in vacuo to yield the title compound.MS: m/z=516 (M+1). HRMS: m/z=516.2601; calculated m/z=516.2606 forC₂₉H₃₄N₅O₄.

EXAMPLE 17

2-[(4aR,9aS)-3-Oxo-2,3,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-4(4-aH)-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

Essentially following the procedures described for Example 10, but using[(4aR,9aS)-3-oxo-2,3,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-4(4aH)-yl]aceticacid (described in Intermediate 39) in place of[(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetic acidhydrochloride, the title compound was obtained. MS: m/z=481 (M+1). HRMS:m/z=481.1865; calculated m/z=481.1871 for C₂₈H₂₅N₄O₄.

EXAMPLE 18

1-(2-Oxo-5-phenylpiperazin-1-yl)-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]cyclopropanecarboxamide

Essentially following the procedures described for Example 10, but using1-(2-oxo-5-phenylpiperazin-1-yl)cyclopropanecarboxylic acid (describedin Intermediate 40) in place of[(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetic acidhydrochloride, the title compound was obtained. MS: m/z=494 (M+1). HRMS:m/z=494.2184; calculated m/z=494.2187 for C₂₉H₂₈N₅O₃.

EXAMPLE 19

2-[(8S)-8-(3,5-Difluorophenyl)-6-oxo-7-azaspiro[4.5]dec-7-yl]-N-(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2-yl)acetamide

A mixture of[(8S)-8-(3,5-difluorophenyl)-6-oxo-7-azaspiro[4.5]dec-7-yl]acetic acid(21 mg, 0.067 mmol, described in Intermediate 86),(±)-2-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(17 mg, 0.067 mmol, described in Intermediate 43), PyClu (28 mg, 0.080mmol), and N,N N-diisopropylethylamine (0.058 mL, 0.33 mmol) in THF (1mL) was stirred at ambient temperature for 16 h. The reaction mixturewas purified directly by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1.Lyophilization provided the title compound as the TFA salt. MS: m/z=558(M+1). HRMS: m/z=558.2313; calculated m/z=558.2311 for C₃₁H₃₀F₂N₅O₃.

EXAMPLE 20

2-[(8S)-8-(3,5-Difluorophenyl)-6-oxo-7-azaspiro[4.5]dec-7-yl]-N-(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)acetamide,isomer A

A mixture of[(8S)-8-(3,5-difluorophenyl)-6-oxo-7-azaspiro[4.5]dec-7-yl]acetic acid(50 mg, 0.16 mmol, described in Intermediate 86),3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,isomer A (39 mg, 0.16 mmol, described in Intermediate 41), HATU (88 mg,0.23 mmol), and N,N N-diisopropylethylamine (0.135 mL, 0.77 mmol) in DMF(1 mL) was stirred at ambient temperature for 16 h. NH₄OH (10 drops) wasadded and the reaction mixture was purified directly by HPLC using areversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Lyophilization provided thetitle compound as the TFA salt. MS: m/z=558 (M+1). HRMS: m/z=558.2301;calculated m/z=558.2311 for C₃₁H₃₀F₂N₅O₃.

EXAMPLE 21

2-[(8S)-8-(3,5-Difluorophenyl)-6-oxo-7-azaspiro[4.5]dec-7-yl]-N-(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)acetamide,isomer A

A mixture of[(8S)-8-(3,5-difluorophenyl)-6-oxo-7-azaspiro[4.5]dec-7-yl]acetic acid(128 mg, 0.395 mmol, described in Intermediate 86),3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,isomer A (66.5 mg, 0.264 mmol, described in Intermediate 42), HATU (160mg, 0.422 mmol), and N-methylmorpholine (0.087 mL, 0.791 mmol) in DMF (1mL) was stirred at ambient temperature for 18 h. The reaction mixturewas purified directly by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1.Lyophilization provided the title compound as the TFA salt. MS: m/z=558(M+1). HRMS: m/z=558.2334; calculated m/z=558.2311 for C₃₁H₃₀F₂N₅O₃.

The examples appearing in the following tables were prepared by analogyto the above examples and intermediates, as described or prepared as aresult of similar transformations with modifications known to thoseskilled in the art. The requisite starting materials and intermediateswere described herein (vide supra), commercially available, known in theliterature, or readily synthesized by one skilled in the art. In somecases, additional synthetic transformations that are well known to thoseskilled in the art were utilized after the key amide coupling to provideother products of interest. Straightforward protecting group strategieswere applied in some routes. Some of the examples described in thetables were synthesized as mixtures of stereoisomers and subsequentlypurified to give individual isomers. In some cases, relevantexperimental procedures are indicated in the tables.

TABLE 12

LCMS Example R⁶ R⁷ R¹⁰ R¹¹ * % (M + 1) 22 H H H phenyl ± S 447 23 Me MeH 3,4-difluorophenyl ± S 511 24 Me Me H 3,4-difluorophenyl S S 511 25 MeMe H 3,4-difluorophenyl R S 511 26 Me Me H 3,5-difluorophenyl S S 511 27Me Me H 3-methyl-2-thienyl R S 495 28 Me Me H 3-methyl-2-thienyl S S 49529 Me Me Me 3,5-difluorophenyl S S 525 30 H Ph H H ± S 447 31 H Ph H H ±R 447 32 Et Et H 3,5-difluorophenyl S S 539

TABLE 13

Ex- LCMS ample R⁶ R⁷ R⁸ R⁹ A¹ R¹¹ * (M + 1) 33 Me Me H H O phenyl 477 34H H H H S 3,5-difluorophenyl 501 35 H H H H SO₂ 3,5-difluorophenyl 53336 H H Me Me S phenyl 493 37 H H H H SO 3,5-difluorophenyl minor 517 38H H H H SO 3,5-difluorophenyl major 517 39 Me Me H H SO3,5-difluorophenyl minor 545 40 Et Et H H O 3,5-difluorophenyl 541

TABLE 14

LCMS Example R⁶ R⁷ R¹¹ * % (M + 1) 41 H H phenyl ± S 447 42 H H phenyl ±R 447 43 Cl Cl phenyl ± S 515 44 Cl Cl phenyl ± R 515

TABLE 15

Relevant Ex- LCMS experimental ample R⁶ R⁷ R R¹¹ * % (M + 1) procedures45 Me Me OH 3,5-difluoro- S S 527 Ex. 6 phenyl

TABLE 16

Relevant LCMS experimental Example R⁶ R⁷ R¹⁰ R¹¹ * (M + 1) procedures 46Me Me H 3,4-difluorophenyl ± 531 Ex. 10 47 Me Me H 3,4-difluorophenyl R531 Ex. 46 48 Me Me H 3,4-difluorophenyl S 531 Ex. 46 49 Me Me H3,5-difluorophenyl S 531 Ex. 10 50 Me Me H 3-chloro-4-fluorophenyl S 547Ex. 10 51 Me Me H 3-fluoro-4-methylphenyl S 527 Ex. 10 52 Me Me H5-fluoro-2-methylphenyl S 527 Ex. 10 53 Me Me H 4-fluoro-2-methylphenylS 527 Ex. 10 54 Me Me H 4-fluoro-3-methylphenyl S 527 Ex. 10 55 Me Me H5-fluoro-2-methoxyphenyl S 543 Ex. 10 56 Me Me H 3-fluorophenyl S 513Ex. 10 57 Me Me H 4-chloro-3-fluorophenyl S 547 Ex. 10 58 Me Me H3-fluoro-2-methylphenyl S 527 Ex. 10 59 Me Me H 2-methoxyphenyl S 525Ex. 10 60 Me Me H 4-methoxyphenyl S 525 Ex. 10 61 Me Me H3-methoxyphenyl S 525 Ex. 10 62 Me Me Me 3,5-difluorophenyl S 545 Ex. 1063 Me Me H 3,5-dichlorophenyl S 563 Ex. 10 64 Me Me H 3-thienyl S 501Ex. 10 65 Me Me H 2-thienyl S 501 Ex. 10 66 Me Me H 5-chloro-2-thienyl S535 Ex. 10 67 Me Me H 1,3-benzodioxol-5-yl S 539 Ex. 10 68 Me Me H3-fluoro-4-methoxyphenyl S 543 Ex. 10 69 Me Me H 3-chloro-5-fluorophenylS 547 Ex. 10 70 Me Me H phenyl S 495 Ex. 10 71 Me Me H2-trifluoromethylphenyl S 563 Ex. 10 72 Me Me H 4-fluorophenyl S 513 Ex.10 73 Me Me H 2-(methylthio)phenyl S 541 Ex. 10 74 Me Me H cyclohexyl S501 Ex. 10 75 Me Me H cyclopropyl S 459 Ex. 10 76 Me Me H 3-chlorophenylS 529 Ex. 10 77 Me Me H 3,4-dichlorophenyl S 563 Ex. 10 78 Me Me H3-methylphenyl S 509 Ex. 10 79 Me Me H 4-methylphenyl S 509 Ex. 10 80 MeMe H 4-(methylthio)phenyl S 541 Ex. 10 81 Me Me H4-chloro-2-methylphenyl S 543 Ex. 10 82 Me Me H benzyl S 509 Ex. 10 83Me Me H 4-chlorophenyl S 529 Ex. 10 84 Me Me H isopropyl S 461 Ex. 10 85Me Me H 4-trifluoromethylphenyl 563 Ex. 10 86 Me Me H2-(methylsulfonyl)phenyl S 573 Ex. 73 87 Me Me H4-(methylsulfonyl)phenyl S 573 Ex. 80 88 Me Me H 3-trifluoromethylphenyl± 563 Ex. 10 89 Me Me H 6-bromo-2,3,4-trifluorophenyl 627 Ex. 10 90 MeMe H 2-methylphenyl S 509 Ex. 10 91 Me Me H 2,3,4-trifluorophenyl 549Ex. 10 92 Me Me H 3-chloro-2,4-difluorophenyl 565 Ex. 10 93 Me H H3,5-difluorophenyl S 517 Ex. 10 94 Et Et H 3,5-difluorophenyl S 559 Ex.10

TABLE 17

Relevant LCMS experimental Example R⁶ R⁷ A¹ R¹⁰ R¹¹ * (M + 1) procedures95 Me Me O H phenyl R 497 Ex. 6 96 Me H O H phenyl R 483 Ex. 6 97 H H OH phenyl R 469 Ex.6 98 Me Me O H 3,5-difluorophenyl R 533 Ex. 6 99 Et EtO H phenyl R 525 Ex. 6 100 H Me O H phenyl R 483 Ex. 6 101 Me Me O H3,5-difluorophenyl S 533 Ex. 6 102 Me Me S H 3,5-difluorophenyl R 549Ex. 2 103 H Et O H phenyl R 497 Ex. 6 104 Et Et O H 3,5-difluorophenyl R561 Ex. 6 105 Me Me CF₂ H 3,5-difluorophenyl S 567 Ex. 7 106 Me Me1,3-dioxolan-2-yl H 3,5-difluorophenyl S 589 Ex. 7

TABLE 18

Relevant LCMS experimental Example R⁶ R⁷ R¹¹ * (M + 1) procedures 107 MeMe 3,5-difluorophenyl R 545 Ex. 7 108 Et Et 3,5-difluorophenyl S 573 Ex.7 109 Et Et 3,5-difluorophenyl R 573 Ex. 7

TABLE 19

Relevant LCMS experimental Example R⁶ R⁷ R * R¹¹ % (M + 1) procedures110 Me Me H R 3,5-difluorophenyl R 547 Ex. 6 111 Me Me H R3,5-difluorophenyl S 547 Ex. 6 112 Me Me H S 3,5-difluorophenyl R 547Ex. 6 113 Me Me Me S 3,5-difluorophenyl S 561 Ex. 6 114 Et Et H S3,5-difluorophenyl S 575 Ex. 6 115 Et Et H R 3,5-difluorophenyl R 575Ex. 6 116 Et Et H R 3,5-difluorophenyl S 575 Ex. 8 117 Me Me Me R3,5-difluorophenyl R 561 Ex. 6

TABLE 20

Relevant LCMS experimental Example R⁶ R⁷ R * R¹¹ % (M + 1) procedures118 Me Me tert-butoxycarbonyl ± 3,5-difluorophenyl S 646 Ex. 8 119 Me MeH ± 3,5-difluorophenyl S 546 Ex. 8 120 Me Me Me S 3,5-difluorophenyl S560 Ex. 8 121 Me Me H S 3,5-difluorophenyl S 546 Ex. 8 122 Me Me H R3,5-difluorophenyl S 546 Ex. 8 123 Et Et H S 3,5-difluorophenyl S 574Ex. 8 124 Et Et H R 3,5-difluorophenyl S 574 Ex. 8

TABLE 21

Relevant LCMS experimental Example R⁶ R⁷ R¹ R¹¹ * (M + 1) procedures 125Me Me tert-butoxycarbonyl phenyl ± 596 Ex. 12 126 Me Me H phenyl ± 496Ex. 12 127 Me Me tert-butoxycarbonyl phenyl S 596 Ex. 12 128 Me Metert-butoxycarbonyl phenyl R 596 Ex. 12 129 Me Me H phenyl R 496 Ex. 12130 Me Me tert-butoxycarbonyl 3,5-difluorophenyl S 632 Ex. 13 131 Me Metert-butoxycarbonyl 3,5-difluorophenyl R 632 Ex. 13 132 Me Me Me3,5-difluorophenyl R 546 Ex. 13 133 Me Me acetyl 3,5-difluorophenyl R574 Ex. 13 134 Me Me methylsulfonyl 3,5-difluorophenyl R 610 Ex. 13 135H Me Me phenyl ± 496 Ex. 10 136 Me H Me phenyl ± 496 Ex. 10 137 H Bn Mephenyl S 572 Ex. 10 138 H Bn Me phenyl R 572 Ex. 10 139 Et Et Me phenyl± 524 Ex. 10 140 Et Et H phenyl ± 538 Ex. 10 141 Et Et H3,5-difluorophenyl S 560 Ex. 10 142 H Ph Me phenyl S 558 Ex. 10 143 H PhMe phenyl R 558 Ex. 10 144 H i-Pr Me phenyl S 524 Ex. 10 145 H i-Pr Mephenyl R 524 Ex. 10 146 H i-Bu Me phenyl S 538 Ex. 10 147 H i-Bu Mephenyl R 538 Ex. 10 148 i-Bu H Me phenyl S 538 Ex. 10 149 i-Bu H Mephenyl R 538 Ex. 10 150 CH₂CF₃ H H 3,5-diflu6rophenyl R 586 Ex. 10 151CH₂CF₃ H H 3,5-difluorophenyl S 586 Ex. 10 152 H CH₂CF₃ H3,5-difluorophenyl R 586 Ex. 10 153 Me Me PhCH₂ 3,5-difluorophenyl R 622Ex. 13 154 Me Me CF₃CH₂ 3,5-difluorophenyl R 614 Ex. 13 155 Me Me H3,5-difluorophenyl S 532 Ex. 13

TABLE 22

Relevant LCMS experimental Example R¹ n R¹⁰ R¹¹ * (M + 1) procedures 156H 3 H phenyl R 522 Ex. 10 157 H 3 H phenyl S 522 Ex. 10 158 Me 1 Hphenyl ± 508 Ex. 10 159 Me 2 H phenyl ± 522 Ex. 10 160tert-butoxycarbonyl 3 H 3,5-difluorophenyl R 658 Ex. 12 161 H 3 H3,5-difluorophenyl S 558 Ex. 12 162 H 4 H 3,5-difluorophenyl R 572 Ex.12 163 H 4 H 3,5-difluorophenyl S 572 Ex. 12 164 H 3 H2-bromo-3,5-difluorophenyl R 636 Ex. 10 165 H 3 H4-bromo-3,5-difluorophenyl R 636 Ex. 10 166 H 4 Me 3,5-difluorophenyl R586 Ex. 13 167 H 4 Me 3,5-difluorophenyl S 586 Ex. 13 168 H 5 Me3,5-difluorophenyl R 600 Ex. 13 169 H 5 Me 3,5-difluorophenyl S 600 Ex.13 170 tert-butoxycarbonyl 3 Me 3,5-difluorophenyl R 672 Ex. 12 171tert-butoxycarbonyl 3 Me 3,5-difluorophenyl S 672 Ex. 12 172 H 3 Me3,5-difluorophenyl R 572 Ex. 12 173 H 3 Me 3,5-difluorophenyl S 572 Ex.12 174 tert-butoxycarbonyl 3 H 3,5-difluorophenyl S 658 Ex. 12

TABLE 23

Relevant LCMS experimental Example R⁶ # R¹¹ * (M + 1) procedures 175 H Sphenyl R 508 Ex. 10 176 H S phenyl S 508 Ex. 10 177 H R phenyl R 508 Ex.10 178 H R phenyl S 508 Ex. 10 179 Me S phenyl R 522 Ex. 10 180 Me Sphenyl S 522 Ex. 10 181 Me S 3,5-difluorophenyl R 558 Ex. 10 182 Me S3,5-difluorophenyl S 558 Ex. 10

TABLE 24

Relevant LCMS experimental Example R⁶ R⁷ R¹ R² # R¹¹ * (M + 1)procedures 183 Me Me H Me R phenyl R 510 Ex. 10 184 Me Me H Me S phenylS 510 Ex. 10 185 Me Me H Me R 3,5-difluorophenyl R 546 Ex. 10 186 Me MeH Me S 3,5-difluorophenyl S 546 Ex. 10

TABLE 25

Relevant Ex- LCMS experimental ample R¹ X R¹⁰ R¹¹ * (M + 1) procedures187 H O H 3,5- R 574 Ex. 10 difluorophenyl 188 H O H 3,5- S 574 Ex. 10difluorophenyl

TABLE 26

Relevant LCMS experimental Example R¹ n X * (M + 1) procedures 189tert-butoxycarbonyl 3 F R 684 Ex. 13 190 tert-butoxycarbonyl 3 F S 684Ex. 13 191 H 3 F R 584 Ex. 13 192 H 3 F S 584 Ex. 13 193tert-butoxycarbonyl 3 H ± 648 Ex. 13 194 H 3 H ± 548 Ex. 13

TABLE 27

Relevant LCMS experimental Example R¹ n X * (M + 1) procedures 195tert-butoxycarbonyl 3 F ± 658 Ex. 13 196 H 3 F ± 558 Ex. 13

TABLE 28

Relevant LCMS experimental Example R¹ (M + 1) procedures 197tert-butoxycarbonyl 602 Ex. 13 198 H 502 Ex. 13

TABLE 29

Relevant LCMS experimental Example X Y Z n R¹¹ * % (M + 1) procedures199 CH₂ CH₂ CH₂ 1 3,5-difluorophenyl S 537 Ex. 10 200 CH₂ CH₂ O 23,5-difluorophenyl S 553 Ex. 10 201 CH₂ CH₂ CH₂ 2 3,5-difluorophenyl S551 Ex. 10 202 NEt CH₂ CH₂ 1 3,5-difluorophenyl S R 566 Ex. 10 203 NHCH₂ CH₂ 1 3,5-difluorophenyl S R 538 Ex. 10

TABLE 30

Relevant LCMS experimental Example X Y Z n R¹¹ * % (M + 1) procedures204 CH₂ CH₂ CH₂ 1 3,5-difluorophenyl S 557 Ex. 10 205 CH₂ CH₂ NH 23,5-difluorophenyl S 572 Ex. 10 206 CH₂ CH₂ NMe 2 3,5-difluorophenyl S586 Ex. 10 207 CH₂ bond bond 1 phenyl ± 493 Ex. 10 208 CH₂ CH₂ O 23,5-difluorophenyl S 573 Ex. 10 209 NH CH₂ CH₂ 1 3,5-difluorophenyl S R558 Ex. 10 210 NCO₂CH₂Ph CH₂ CH₂ 1 3,5-difluorophenyl S R 692 Ex. 10 211NMe CH₂ CH₂ 1 3,5-difluorophenyl S R 572 Ex. 10 212 NCH₂CF₃ CH₂ CH₂ 13,5-difluorophenyl S R 640 Ex. 10 213 CH₂ CH₂ NCO₂CH₂Ph 23,5-difluorophenyl S 706 Ex. 10

TABLE 31

Relevant LCMS experimental Example X Y Z A¹ n R¹⁰ R¹¹ * % (M + 1)procedures 214 CH₂ CH₂ CH₂ CH₂ 1 H 3,5-difluorophenyl S ± 558 Ex. 20 215CH₂ CH₂ CH₂ CH₂ 1 H 3,5-difluorophenyl S Isomer B 558 Ex. 20 216 CH₂ CH₂CH₂ NH 1 H 3,5-difluorophenyl R Isomer A 559 Ex. 20 217 CH₂ CH₂ O CH₂ 2H 3,5-difluorophenyl S Isomer A 574 Ex. 20 218 CH₂ CH₂ CH₂ NH 1 Me3,5-difluorophenyl R Isomer A 573 Ex. 20

TABLE 32

Relevant LCMS experimental Example X Y Z A¹ n R¹⁰ R¹¹ * % (M + 1)procedures 219 CH₂ CH₂ CH₂ CH₂ 1 H 3,5-difluorophenyl S Isomer B 559 Ex.21 220 CH₂ CH₂ CH₂ NH 1 H 3,5-difluorophenyl R Isomer A 559 Ex. 21 221CH₂ CH₂ CH₂ NH 1 H 3,5-difluorophenyl R Isomer B 559 Ex. 21 222 CH₂ CH₂CH₂ NH 1 H 3,5-difluorophenyl R ± 559 Ex. 21 223 CH₂ CH₂ O CH₂ 2 H3,5-difluorophenyl S Isomer A 574 Ex. 21 224 CH₂ CH₂ CH₂ NH 1 Me3,5-difluorophenyl R Isomer A 573 Ex. 21

TABLE 33

Relevant LCMS experimental Example R⁶ X R¹¹ (M + 1) procedures 225 Et Ophenyl 536 Ex. 10 226 Et H, H phenyl 522 Ex. 10

Although specific enantiomers and diastereomers appear in the aboveExamples and Intermediates, it is well understood by those skilled inthe art that modifications to reaction conditions and reagents (forexample, but not limited to: using the opposite chirality for startingmaterials; different catalysts; using the opposite chirality forreagents; choosing to use a different enantiomer or diastereomersubsequent to a chiral resolution) will provide alternative enantiomersand diastereomers, all of which are included in the spirit and scope ofthe invention. It is intended that all of the possible optical isomersand diastereomers in mixtures and as pure or partially purifiedcompounds are included within the ambit of this invention. The presentinvention is meant to comprehend all such isomeric forms of thesecompounds.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A compound of the formula I:

wherein: A¹ is selected from: (1) —O—, (2) —S(O)_(v)—, (3)—Si(OR^(a))—C₁₋₄-alkyl-, where alkyl is unsubstituted or substitutedwith 1-5 halo, (4) —Si(C₁₋₄alkyl)₂, where each alkyl is independentlyunsubstituted or substituted with 1-5 halo-, (5) —CR⁶R⁷—, (6) —N(R⁸)—,(7) —(C═O)—, (8) —C(R⁸)(R^(a))—, (9) —C(N(R^(b))—SO₂R^(d))(R^(a))—, (10)—C(N(R^(b))(C═O)R^(a))(R^(a))—, (11) —C(N(R^(b))(C═O)OR^(a))(R^(a))—,(12) —CR¹⁰R¹¹—, and (13) —N(R¹¹)—; A² is selected from: (1) —CR⁶R⁷—, (2)—CR¹⁰R¹¹—, and (3) —(C═O)—; A³ is selected from: (1) —CR⁶R⁷—, (2)—N(R⁸)—, (3) —CR¹⁰R¹¹—, and (4) —N(R¹¹)—; A⁴ is (6) a bond between A²and A³; E^(a) is selected from: (1) —C(R^(5a))═, (2) —N═, and (3)—(N⁺—O⁻)═; E^(b) is selected from: (1) —C(R^(5b))═, (2) —N═, and (3)—(N⁺—O⁻)═; E^(c) is selected from: (1) —C(R^(5c))═, (2) —N═, and (3)—(N⁺—O⁻)═; Q is —C(R^(a))₂—; R⁴ is selected from: (1) hydrogen, (2)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 substituentseach independently selected from: (a) halo, (b) —C₃₋₆cycloalkyl, (c)—CF₃, and (d) —O—R^(a), (3) —C₃₋₆cycloalkyl, (4) benzyl, and (5) phenyl;R^(5a), R^(5b) and R^(5c) are each independently selected from: (1)hydrogen, (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6halo, (3) halo, (4) —OR^(a), and (5) —CN; R⁶ and R⁷ are eachindependently selected from: (1) hydrogen, (2) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) halo, (b) —OR^(a), (c) —C₃₋₆cycloalkyl, (d) phenyl orheterocycle, wherein said heterocycle is selected from: pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl,pyrrolidinyl, thienyl, morpholinyl, thiazolyl, indolyl, indazolyl,benzimidazolyl and oxazolyl, which phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (i) halo, (ii) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-5 halo, (iii) —OR^(a), (iv) —NR^(b)R^(c), (v) —CN,and (vi) oxo; (e) —CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (g) —S(O)_(v)R^(d),(h) —CN, (i) —NR^(b)R^(c), (j) —N(R^(b))C(═O)R^(a), (k)—N(R^(b))SO₂R^(d), (l) —CF₃, (m) —O—CO₂R^(d), (n) —O—(C═O)—NR^(b)R^(c),(o) —NR^(b)—(C═O)—NR^(b)R^(c), and (p) —C(═O)R^(a), (3) —C₃₋₈cycloalkyl,which is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) halo, (b) —CN, (c) —C₁₋₄-alkyl, whichis unsubstituted or substituted with 1-3 halo, and (d) —OR^(a), (4)phenyl or heterocycle, wherein said heterocycle is selected from:pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl,pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenylor heterocycle is unsubstituted or substituted with 1-5 substituentseach independently selected from: (a) halo, (b) —OR^(a), (c)—C₃₋₆cycloalkyl, (d) phenyl, which is unsubstituted or substituted with1-5 substituents each independently selected from: (i) halo, (ii)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 halo, and(iii) —OR^(a), (e) —CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (g) —S(O)_(v)R^(d),(h) —CN, (i) —NR^(b)R^(c), (j) —N(R^(b))C(═O)R^(a), (k)—N(R^(b))SO₂R^(d), (l) —O—CO₂R^(d), (m) —O—(C═O)—NR^(b)R^(c), (n)—NR^(b)—(C═O)—NR^(b)R^(c), (o) —C(═O)R^(a), (p) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, and (q) oxo; (5) halo, (6)—OR^(a), (7) —CN, (8) —CO₂R^(a) (9) —N(R^(b))C(═O)R^(a) (10)—NR^(b)R^(c), (11) —C(═O)NR^(b)R^(c), and (12) —O(C═O)R^(a); or R⁶ andR⁷ and the carbon atom or atoms to which they are attached join to forma ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, dioxolanyl, dioxanyl,aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiapyranyl, oxetanyl, thietanyl and tetrahydrothienyl,wherein the sulfur is optionally oxidized to the sulfone or sulfoxide,which ring is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-3 substituents each independently selected from: (i)halo, (ii) —OR^(a), (iii) —C₃₋₆cycloalkyl, (iv) —CO₂R^(a), (v)—NR^(b)R^(c), (vi) —S(O)_(v)R^(d), (vii) —C(═O)NR^(b)R^(c), and (viii)phenyl, (b) —C₃₋₆cycloalkyl, wherein the C₃₋₆cycloalkyl group isoptionally fused to the ring, and which C₃₋₆cycloalkyl group isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (i) halo, (ii) —OR^(a), (iii) —C₃₋₆cycloalkyl, (iv)—CO₂R^(a), (v) —NR^(b)R^(c), (vi) —-S(O)_(v)R^(d), (vii)—C(═O)NR^(b)R^(c), and (viii) phenyl, (c) phenyl or heterocycle, whereinheterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,morpholinyl, imidazolyl, furanyl, tetrahydrofuranyl, thiazolyl andoxazolyl, wherein the phenyl or heterocycle is optionally fused to thering, and which phenyl or heterocycle is unsubstituted or substitutedwith 1-5 substituents each independently selected from: (i) halo, (ii)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (iii)—OR^(a), (iv) —CO₂R^(a), (v) —O(C═O)R^(a), (vi) —CN, (vii) —NR^(b)R^(c),(viii) oxo, (ix) —C(═O)NR^(b)R^(c), (x) —N(R^(b))C(═O)R^(a), (xi)—N(R^(b))CO₂R^(a), (xii) —O(C═O)NR^(b)R^(c), and (xiii) —S(O)_(v)R^(d),(d) —OR^(a), (e) —CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (g) —S(O)_(v)R^(d),(h) —CN, (i) halo, (j) —NR^(b)R^(c), (k) —N(R^(b))C(═O)R^(a), (l)—N(R^(b))SO₂R^(d), (m) —O—CO₂R^(d), (n) —O—(C═O)—NR^(b)R^(c), (o)—NR^(b)—(C═O)—NR^(b)R^(c), (p) —C(═O)R^(a), and (q) oxo; R⁸ isindependently selected from: (1) hydrogen, (2) —C(═O)R^(a), (3)—CO₂R^(a), (4) —S(═O)R^(d), (5) —SO₂R^(d), (6) —C(═O)NR^(b)R^(c), (7)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 substituentseach independently selected from: (a) halo, (b) —OR^(a), (c)—C₃₋₆cycloalkyl, (d) phenyl or heterocycle, wherein said heterocycle isselected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyland oxazolyl, which phenyl or heterocycle is unsubstituted orsubstituted with 1-5 substituents each independently selected from: (i)halo, (ii) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5halo, and (iii) —OR^(a), (iv) —NR^(b)R^(c), (v) —C(═O)R^(a), (vi)—CO₂R^(a), and (vii) oxo, (e) —CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (g)—S(O)_(v)R^(d), (h) —CN, (i) —NR^(b)R^(c), (j) —N(R^(b))C(═O)R^(a), (k)—N(R^(b))SO₂R^(d), (l) —CF₃, (m) —O—CO₂R^(d), (n) —O—(C═O)—NR^(b)R^(c),(o) —NR^(b)—(C═O)—NR^(b)R^(c) and (p) —C(═O)R^(a), (8) —C₃₋₆cycloalkyl,which is unsubstituted or substituted with 1-6 substituents eachindependently selected from: (a) halo, (b) —CN, (c) —OR^(a), and (d)C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 halo; or R⁷and R⁸ and the atoms to which they are attached join to form a 4-, 5-,6- or 7-membered alkyl- or heteroalkyl-ring optionally containing anadditional heteroatom selected from N, O, and S, wherein the sulfur isoptionally oxidized to the sulfone or sulfoxide, which ring isunsubstituted or substituted with 1-4 substituents each independentlyselected from: (a) halo, (b) phenyl, which is unsubstituted orsubstituted with 1-3 substituents each independently selected from:halo, OR^(a), CN, and —C(═O)OR^(a), (c) —OR^(a), and (d) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-6 halo; R¹⁰ isindependently selected from: (1) hydrogen, (2) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) halo, (b) —OR^(a), (c) —CN, (d) phenyl, and (e)—C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-6 halo,(3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-6halo; R¹¹ is independently selected from the group consisting of:phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl,anthryl, azepinyl, azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl,benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, 1,3-benzodioxolyl, benzothiazolyl, benzothienyl,benzoxazolyl, benzopyrazolyl, benzotriazolyl, chromanyl, cinnolinyl,dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl,furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl,isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl,tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, thienyl, triazolyl, isoxazolyl, tetrahydrothienyl,tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, and thietanyl, whereR¹¹ is unsubstituted or substituted with 1-5 substituents eachindependently selected from R¹², R¹³, R¹⁴, R^(15a) and R^(15b); R¹²,R¹³, R¹⁴, R^(15a) and R^(15b) are each independently selected from: (1)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 substituentseach independently selected from: (a) halo, (b) —OR^(a), (c)—C₃₋₆cycloalkyl, (d) phenyl or heterocycle, wherein said heterocycle isselected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyland oxazolyl, which phenyl or heterocycle is unsubstituted orsubstituted with 1-5 substituents each independently selected from: (i)halo, (ii) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5halo, and (iii) —OR^(a), (e) —CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (g)—S(O)_(v)R^(d), (h) —CN, (i) —NR^(b)R^(c), (j) —N(R^(b))C(═O)R^(a), (k)—N(R^(b))SO₂R^(d), (l) —CF₃, (m) —O—CO₂R^(d), (n) —O—(C═O)—NR^(b)R^(c),(o) —NR^(b)—(C═O)—NR^(b)R^(c) and (p) —C(═O)R^(a), (2) —C₁₋₆cycloalkyl,which is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) halo, (b) —CN, (c) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (d) —OR^(a), and (e) phenyl,which is unsubstituted or substituted with 1-5 substituents where thesubstituents are each independently selected from: (i) —OR^(a), (ii)halo, (iii) —CN, and (iv) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-5 halo, (3) phenyl or heterocycle, wherein saidheterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) halo, (b) —OR^(a), (c) —C₃₋₆cycloalkyl, (d) phenyl,which is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (i) halo, (ii) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, and (iii) —OR^(a), (e)—CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (g) —S(O)_(v)R^(d), (h) —CN, (i)—NR^(b)R^(c), (j) —N(R^(b))C(═O)R^(a), (k) —N(R^(b))SO₂R^(d), (l)—O—CO₂R^(d), (m) —O—(C═O)—NR^(b)R^(c), (n) —NR^(b)—(C═O)—NR^(b)R^(c),(o) —C(═O)R^(a), and (p) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 halo, (4) halo, (5) oxo, (6) —OR^(a), (7) —CN, (8)—CO₂R^(a), (9) —C(═O)R^(a), (10) —NR^(b)R^(c), (11) —S(O)_(v)R^(d), (12)—C(═O)NR^(b)R^(c), (13) —O—CO₂R^(d), (14) —N(R^(b))CO₂R^(d), (15)—O—(C═O)—NR^(b)R^(c), (16) —NR^(b)—(C═O)—NR^(b)R^(c), (17)—SO₂NR^(b)R^(c), (18) —N(R^(b))SO₂R^(d), or R^(15a) and R^(15b) and theatom(s) to which they are attached join to form a ring selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thietanyl and tetrahydrothienyl, wherein the sulfur isoptionally oxidized to the sulfone or sulfoxide, which ring isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-3 substituents each independently selected from: (i) halo, (ii)—OR^(a), (iii) —C₃₋₆cycloalkyl, (iv) —CO₂R^(a), (v) —NR^(b)R^(c), (vi)—S(O)_(v)R^(d), (vii) —C(═O)NR^(b)R^(c), and (viii) phenyl, (b) phenylor heterocycle, wherein said heterocycle is selected from: pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl,pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenylor heterocycle is unsubstituted or substituted with 1-5 substituentseach independently selected from: (i) halo, (ii) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, and (iii) —OR^(a), (c)—OR^(a), (d) halo, (e) —CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (g)—S(O)_(v)R^(d), (h) —CN, (i) —NR^(b)R^(c), (j) —N(R^(b))C(═O)R^(a), (k)—N(R^(b))SO₂R^(d), (l) —O—CO₂R^(d), (m) —O—(C═O)—NR^(b)R^(c), (n)—NR^(b)—(C═O)—NR^(b)R^(c) and (o) —C(═O)R^(a); R^(PG) is independentlyselected from: (1) hydrogen, (2) —C₁₋₆alkyl which is unsubstituted orsubstituted with 1-5 halo, (3) —CH₂OR^(a), (4) —CH₂—O—CH₂CH₂Si(CH₃)₃,(5) —CH₂OP(═O)(OR^(c))₂, (6) —(CH₂)_(k)-phenyl, which is unsubstitutedor substituted with 1-3 substituents each independently selected from:(a) halo, (b) —OR^(a), (c) —CN, and (d) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo; J is independently selectedfrom: (1) ═C(R^(16a))—, (2) —CR¹⁷R¹⁸—, (3) —C(═O)—, and (4) —N(R^(b))—;Y is independently selected from: (1) ═C(R^(16b))—, (2) —CR¹⁷R¹⁸—, (3)—C(═O)—, (4) ═N—, and (5) —N(R^(16b))—; R¹⁷ and R¹⁸ are eachindependently selected from: (1) hydrogen, (2) halo, (3) —OR^(a), (4)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-4 substituentseach independently selected from: (a) halo, (b) —OR^(a), (c) —CN, (d)phenyl or heterocycle, wherein said heterocycle is selected frompyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl,piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (i) —OR^(a), (ii) halo, (iii) —CN, (iv) —C₁₋₆alkyl whichis unsubstituted or substituted with 1-6 halo, (5) phenyl or heterocyclewherein heterocycle is selected from pyridyl, pyrimidinyl, thienyl,pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl,morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, whichphenyl or heterocycle is unsubstituted or substituted with 1-5substituents each independently selected from: (a) halo, (b) —CN, (c)—OR^(a), (d) nitro, (e) —C₁₋₆alkyl which is unsubstituted or substitutedwith 1-6 halo; or R¹⁷ and R¹⁸ and the atom to which they are attachedjoin to form a 4-, 5-, or 6-membered ring optionally containing aheteroatom selected from N, O, and S, wherein the sulfur is optionallyoxidized to the sulfone or sulfoxide, which ring is unsubstituted orsubstituted with 1-4 substituents each independently selected from: (a)halo, (b) —OR^(a), (c) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-6 halo, and (d) phenyl; R^(16a) and R^(16b) are eachindependently selected from: (1) hydrogen, (2) —C₁₋₄-alkyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) halo, (b) —OR^(a), (c) —C₃₋₆cycloalkyl, (d) phenyl orheterocycle, wherein said heterocycle is selected from: imidazolyl,oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl,piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, isoxazolyl andmorpholinyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-3 substituents each independently selected from: (i) halo, (ii)—OR^(a), (iii) —CN, and (iv) C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 halo, (3) phenyl or heterocycle, whereinheterocycle is selected from: imidazolyl, oxazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydrofuryl, piperidinyl,piperazinyl, pyrrolidinyl, azetidinyl, thiazolyl, thienyl, triazolyl,isoxazolyl and morpholinyl, which phenyl or heterocycle is unsubstitutedor substituted with 1-3 substituents each independently selected from:(a) halo, (b) —OR^(a), (c) —C₃₋₆cycloalkyl, (d) —C₁₋₄-alkyl which isunsubstituted or substituted with 1-6 halo, and (e) phenyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (i) halo, (ii) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 halo, and (iii) —OR^(a), (4) halo, (5) —OR^(a), (6)—CN, (7) —CO₂R^(a), (8) —NR^(b)R^(c), and (9) —C(═O)NR^(b)R^(c); orR^(16a) and R^(16b) and the atom(s) to which they are attached join toform a ring selected from cyclopentenyl, cyclohexenyl, phenyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, dihydrofuranyl,dihydropyranyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, triazolyl, thienyl, dihydrothienyl and dihydrothiopyranyl,which ring is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-3 substituents each independently selected from: (i)halo, (ii) —OR^(a), (iii) —C₃₋₆cycloalkyl, (iv) phenyl or heterocycle,wherein heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl andmorpholinyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-5 substituents each independently selected from:  (I) —OR^(a), (II) halo,  (III) —CN, and  (IV) —C₁₋₆alkyl which is unsubstituted orsubstituted with 1-6 halo, (v) —CO₂R^(a), (vi) —NR^(b)R^(c), (vii)—S(O)_(v)R^(d), (viii) —C(═O)NR^(b)R^(c), (ix) —N(R^(b))CO₂R^(a), and(x) —N(R^(b))SO₂R^(d), (b) phenyl or heterocycle, wherein saidheterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, thienyland morpholinyl, which phenyl or heterocycle is unsubstituted orsubstituted with 1-5 substituents each independently selected from: (i)halo, (ii) —OR^(a), (iii) —CN, and (iv) —C₁₋₆alkyl which isunsubstituted or substituted with 1-6 halo, (c) halo, (d)—S(O)_(v)R^(d), (e) —OR^(a), (f) —CN, (g) —C(═O)R^(a), (h) —NR^(b)R^(c),(i) —C(═O)NR^(b)R^(c), (j) —CO₂R^(a), (k) —(NR^(b))CO₂R^(a), (l)—O—(C═O)—NR^(b)R^(c), (m) —(NR^(b))—(C═O)—NR^(b)R^(c), (n) oxido, (o)oxo, and (p) —(NR^(b))SO₂R^(d); R^(a) is independently selected from:(1) hydrogen, (2) C₁₋₆alkyl, which is unsubstituted or substituted with1-7 substituents each independently selected from: (a) halo, (b)—O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 halo, (c)hydroxyl, (d) —CN, and (e) phenyl or heterocycle wherein saidheterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl,piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl,morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, whichphenyl or heterocycle is unsubstituted or substituted with 1-3substituents each independently selected from: (i) halo, (ii)—O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 halo, (iii)—CN, (iv) nitro, (v) hydroxyl, and (vi) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, (3) phenyl or heterocyclewherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl,pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl,pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl andpyrazinyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-3 substituents each independently selected from: (a) halo, (b)—CN, (c) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6halo, (d) nitro, (e) hydroxyl, and (f) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, and (4) —C₃₋₆cycloalkyl,which is unsubstituted or substituted with 1-6 halo; R^(b) and R^(c) areindependently selected from: (1) hydrogen, (2) C₁₋₆alkyl, which isunsubstituted or substituted with 1-7 substituents each independentlyselected from: (a) halo, (b) —OR^(a), (c) —CN, (d) —CO₂R^(a), (e) phenylor heterocycle, wherein said heterocycle is selected from pyridyl,pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl,piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (i) halo, (ii) —OR^(a), (iii) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, and (iv) nitro, (3) phenylor heterocycle, wherein said heterocycle is selected from pyridyl,pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl,piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (a) halo, (b) —OR^(a), (c) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, (d) —C₃₋₆cycloalkyl, whichis unsubstituted or substituted with 1-6 halo, (e) —CN, and (f)—CO₂R^(a), (4) —C₃₋₆cycloalkyl, which is unsubstituted or substitutedwith 1-6 halo;  or R^(b) and R^(c) and the nitrogen to which they areattached join to form a 4-, 5-, or 6-membered ring optionally containingan additional heteroatom selected from N, O, and S, wherein the sulfuris optionally oxidized to the sulfone or sulfoxide, which ring isunsubstituted or substituted with 1-4 substituents each independentlyselected from: (a) halo, (b) —OR^(a), and (c) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, and (d) phenyl; R^(d) isindependently selected from: (1) C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-4 substituents each independently selected from: (a)halo, (b) —OR^(a), (c) —CO₂R^(a), (d) —CN, and (e) phenyl orheterocycle, wherein said heterocycle is selected from pyridyl,pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl,piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (i) halo, (ii) —OR^(a), (iii) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, and (iv) nitro, (2) phenylor heterocycle, wherein said heterocycle is selected from pyridyl,pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl,piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (a) halo, (b) —OR^(a), (c) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, (d) —C₃₋₆cycloalkyl, whichis unsubstituted or substituted with 1-6 halo (e) —CN, and (f)—CO₂R^(a), and (3) —C₃₋₆cycloalkyl, which is unsubstituted orsubstituted with 1-6 halo; R^(e) and R^(f) are independently selectedfrom: (1) hydrogen, (2) —C₁₋₄-alkyl, which is unsubstituted orsubstituted with 1-6 halo, (3) phenyl, and (4) benzyl; or where R^(e)and R^(f) and the atom to which they are attached join to form a 3-, 4-,5-, or 6-membered ring optionally containing a heteroatom selected fromN, O, and S, wherein the sulfur is optionally oxidized to the sulfone orsulfoxide, which ring is unsubstituted or substituted with 1-4substituents each independently selected from: (a) halo, (b) —OR^(a),(c) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 halo, and(d) phenyl; m is 1; n is 1; v is 0, 1, or 2; k is 0, 1, or 2; or apharmaceutically acceptable salt, individual enantiomer or diastereomerthereof.
 2. The compound of claim 1 having the formula Ia:

or a pharmaceutically acceptable salt, individual enantiomer ordiastereomer thereof.
 3. The compound of claim 1, wherein A¹ isindependently selected from: (1) —O—, (2) —S(O)—, (3)—Si(OR^(a))(C₁₋₄alkyl), which alkyl is unsubstituted or substituted with1-5 halo, (4) —Si(C₁₋₄alkyl)₂, —Si(C₁₋₄alkyl)₂, where each alkyl isindependently unsubstituted or substituted with 1-5 halo-, (5) —CR⁶R⁷—,(6) —N(R⁸)—, (7) —(C═O)—, (8) —C(R⁸)(R^(a))—, (9)—C(N(R^(b))—SO₂R^(d))(R^(a))—, (10) —C(N(R^(b))(C═O)R^(a))(R^(a))—, (11)—C(N(R^(b))(C═O)OR^(a))(R^(a))—, (12) —CR¹⁰R¹¹—, and (13) —N(R¹¹)—. 4.The compound of claim 1, wherein A² is independently selected from: (1)—CR⁶R⁷—, (2) —CR¹⁰R¹¹—, and (3) —(C═O)—.
 5. The compound of claim 1,wherein A³ is independently selected from: (1) —CR⁶R⁷—, (2) —CR¹⁰R¹¹—,and (3) —N(R¹¹)—.
 6. The compound of claim 1, wherein E^(a) isindependently selected from: (1) —C(R^(5a))═, (2) —N═, and (3)—(N⁺—O⁻)═.
 7. The compound of claim 1, wherein E^(b) is independentlyselected from: (1) —C(R^(5b))═, (2) —N═, and (3) —(N⁺—O⁻)═.
 8. Thecompound of claim 1, wherein E^(c) is independently selected from: (1)—C(R^(5c))═, (2) —N═, and (3) —(N⁺—O⁻)═.
 9. The compound of claim 1,wherein R⁴ is selected from: hydrogen and —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 fluoro.
 10. The compound of claim1, wherein R^(5a), R^(5b) and R^(5c) are independently selected fromhydrogen, halo, and —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 fluoro.
 11. The compound of claim 1, wherein R⁶ and R⁷ areindependently selected from: (1) hydrogen, (2) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 substituents where thesubstitutents are each independently selected from: halo, phenyl, and—OR^(a), (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with1-5 fluoro, (4) phenyl or heterocycle, which is unsubstituted orsubstituted with 1-5 halo, (5) halo, (6) —OR^(a), (7) —NR^(b)R^(c), and(8) —O(C═O)R^(a).
 12. The compound of claim 1, wherein R⁶ and R⁷ and thecarbon atom or atoms to which they are attached join to form a ringselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,dioxolanyl, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl,pyrrolidinyl, and piperidinyl, which ring is unsubstituted orsubstituted with 1-6 substituents each independently selected from: (1)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-3 substituentswhere the substitutents are each independently selected from: halo,—OR^(a), and phenyl, (2) —C₃₋₆cycloalkyl, wherein the C₃₋₆cycloalkylgroup is optionally fused to the ring, and which C₃₋₆cycloalkyl group isunsubstituted or substituted with 1-3 substituents each independentlyselected from: halo, —OR^(a), and phenyl, (3) phenyl or heterocycle,wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,morpholinyl, thiazolyl and oxazolyl, wherein the phenyl or heterocycleis optionally fused to the ring, and which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: halo, —OR^(a), and —C₁₋₄-alkyl, which is unsubstituted orsubstituted with 1-5 fluoro, (4) halo, (5) oxo, (6) —CO₂R^(a), and (7)—C(═O)R^(a).
 13. The compound of claim 1, wherein R⁸ is selected from:hydrogen, —C(═O)R^(a), —CO₂R^(a), —SO₂R^(d), and —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 fluoro.
 14. The compound of claim1, wherein R⁸ and R⁷ and the atoms to which they are attached join toform a 4-, 5-, 6- or 7-membered alkyl- or heteroalkyl-ring optionallycontaining an additional heteroatom selected from N, O, and S, whereinthe sulfur is optionally oxidized to the sulfone or sulfoxide, whichring is unsubstituted or substituted with 1-4 substituents eachindependently selected from: (1) halo, (2) phenyl, which isunsubstituted or substituted with 1-3 substituents each independentlyselected from: halo, OR^(a), CN, and —C(═O)OR^(a), (3) —OR^(a), and (4)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 halo.
 15. Thecompound of claim 1, wherein R¹⁰ is selected from: hydrogen, and—C₁₋₆alkyl, which is unsubstituted or substituted with fluoro.
 16. Thecompound of claim 1, wherein R¹¹ is independently selected from thegroup consisting of: phenyl, naphthyl, tetrahydronaphthyl, indanyl,biphenyl, phenanthryl, anthryl, azepinyl, azepanyl, azetidinyl,benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl,benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, chromanyl,cinnolinyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl,furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl,isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl,tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, thienyl, triazolyl, isoxazolyl, tetrahydrothienyl,tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, and thietanyl, whereR¹¹ is unsubstituted or substituted with 1-5 substituents eachindependently selected from R¹², R¹³, R¹⁴, R^(15a) and R^(15b).
 17. Thecompound of claim 1, wherein R^(PG) is selected from: (1) hydrogen, (2)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-3 halo, (3)—CH₂OR^(a), (4) —CH₂—O—CH₂CH₂Si(CH₃)₃, and (5) CH₂OP(═O)(OR^(c))₂wherein R^(a) is defined herein.
 18. The compound of claim 1, wherein Jis ═C(R^(16a))—, —CR¹⁷R¹⁸— or —N(R^(b))—.
 19. The compound of claim 1,wherein Y is ═C(R^(16b))—, —CR¹⁷R¹⁸— or —C(═O)—.
 20. The compound ofclaim 1, wherein R^(16a) and R^(16b) are independently selected from:(1) hydrogen, (2) —C₁₋₄-alkyl, which is unsubstituted or substitutedwith 1-3 substituents each independently selected from: halo, —OR^(a),—C₃₋₆cycloalkyl, and phenyl, (3) phenyl or heterocycle, whereinheterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl,thiazolyl, thienyl, triazolyl, isoxazolyl and morpholinyl, which phenylor heterocycle is unsubstituted or substituted with 1-3 substituentseach independently selected from: —C₁₋₄-alkyl which is unsubstituted orsubstituted with 1-3 halo, —OR^(a), and halo, (4) halo, (5) OR^(a), and(6) —NR^(b)R^(c).
 21. The compound of claim 1, wherein R^(16a) andR^(16b) and the atom(s) to which they are attached join to form a ringselected from cyclohexenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, and thienyl,which ring is unsubstituted or substituted with 1-3 substituents eachindependently selected from: (1) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-3 substituents each independently selected from:halo, OR^(a), —CO₂R^(a), —NR^(b)R^(c) and CONR^(b)R^(c), (2) phenyl orheterocycle, wherein heterocycle is selected from pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl,pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: halo, OR^(a) and —C₁₋₄-alkyl, which is unsubstituted orsubstituted with 1-3 fluoro, (3) halo, (4) OR^(a), (5) —CN, (6)—NR^(b)R^(c), (7) CONR^(b)R^(c), and (8) oxo.
 22. A compound which is:

or a pharmaceutically acceptable salt, individual enantiomer ordiastereomer thereof.
 23. A compound which is:

or a pharmaceutically acceptable salt, individual enantiomer ordiastereomer thereof.
 24. A pharmaceutical composition which comprisesan inert carrier and the compound of claim 1 or a pharmaceuticallyacceptable salt thereof.
 25. A method for treating headache, migraine orcluster headache in a mammalian patient in need of such which comprisesadministering to the patient a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof.
 26. Amethod of treating migraine headaches, cluster headaches, and headaches,said method comprising the co-administration, to a person in need ofsuch treatment, of: a therapeutically effective amount of the compoundof claim 1 or a pharmaceutically acceptable salt thereof; and atherapeutically effective amount of a second agent selected fromserotonin agonists, analgesics, anti-inflamatory agents,anti-hypertensives and anticonvulsants.